IE57237B1 - Phenethanolamine derivatives - Google Patents

Phenethanolamine derivatives

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Publication number
IE57237B1
IE57237B1 IE965/84A IE96584A IE57237B1 IE 57237 B1 IE57237 B1 IE 57237B1 IE 965/84 A IE965/84 A IE 965/84A IE 96584 A IE96584 A IE 96584A IE 57237 B1 IE57237 B1 IE 57237B1
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IE
Ireland
Prior art keywords
methyl
hydroxy
group
general formula
benzenedimethanol
Prior art date
Application number
IE965/84A
Other versions
IE840965L (en
Original Assignee
Glaxo Group Ltd
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Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=27449465&utm_source=***_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=IE57237(B1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority claimed from GB838310477A external-priority patent/GB8310477D0/en
Priority claimed from GB838317087A external-priority patent/GB8317087D0/en
Priority claimed from GB838329568A external-priority patent/GB8329568D0/en
Priority claimed from GB848401889A external-priority patent/GB8401889D0/en
Application filed by Glaxo Group Ltd filed Critical Glaxo Group Ltd
Publication of IE840965L publication Critical patent/IE840965L/en
Publication of IE57237B1 publication Critical patent/IE57237B1/en

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Abstract

Phenethanolamine derivatives are disclosed of formula wherein m is 2 to 8; n is 1 to 7 provided that m+n is 4 to 12; Ar is phenyl or phenyl substituted by one or two halogen atoms, alkyl or alkoxy groups or by an alkylenedioxy group; R<1> and R<2> are hydrogen or alkyl provided that the sum total of carbon atoms in R<1> and R<2> is not more than 4; and the physiologically acceptable salts and solvates thereof. Also disclosed as novel are compounds of formula Ar(CH2)nO(CH2)mX where X is -CH(R<2>)L, R<2>CO- or -C(R<1>)(R<2>) NHY<1>, where L is a leaving group and Y<1> is H or a group convertible thereto by catalytic hydrogenation.

Description

This invention relates to phenethanolamine compounds having a stimulant action at e2-adrenoreceptors, to processes for their preparation, to pharmaceutical compositions containing them and to their use in medicine.
Certain phenethanolamine compounds are known to possess either stimulant or blocking actions at β-adrenoreceptors. For example, Patent Specification No. 813*)! describes a group of such phenethanolamines of general structure: where, inter alia, Χχ is hydroxyalkyl, Rj and R2 is each a hydrogen atom, and R3 is straight or branched Cj_6 alkyl, aralkyl or aryloxyalkyl. One compound from Within this particular group has been developed for clinical use. This is salbutamol [ (a1-tert-butylamincanethyl) -4-hydroxy-mxylene-«^,e3-diol; Χχ = CH2OH, RT =-H; R2= -H; R3 = t-butyl, above] which at the present time is widely prescribed for the treatment of conditions such as bronchial asthma and chronic bronchitis. The success of salbutamol devolves from its profile of action, in particular its potency, coupled with a selective stimulant action at β2~adrenoreceptors.
All B2~stimulants currently used in clinical practice suffer from the disadvantage that they have a relatively short duration of action when administered by inhalation. A B2-stimulant with a relatively long duration of action would therefore offer a significant advance in the ll* treatment of bronchial asthma and related disorders.
In a search for new β-stimulants with advantageous ' properties, we have now found a novel group of phenethanolamine derivatives, which differ structurally from the group of compounds described in Patent Specification No. 31391 and which in our tests have shown a potent selective stimulant action at Bj-adrenoreceptors, and, in addition, have an advantageous profile of action.
Thus, the present invention provides compounds of the general formula (I) to wherein m is an integer from 2 to 8 and n is an integer from 1 to 7 with the proviso that the sum total of m + n is 4 to 12; Ar represents a phenyl group optionally substituted by one or two substituents selected from halogen atoms, C^_3 alkyl or alkoxy groups, or by an alkylenedioxy group of formula -O(CH-) 0- where p is 1 or 2; and 2 z P R and R each represents a hydrogen atom or a alkyl group with the proviso that the sum total of carbon atoms 1 2 in R and R is not more than 4; and physiologically acceptable salts and solvates (e.g. hydrates) thereof.
It will be appreciated that the compounds of general formula (I) possess one or two asymmetric carbon atoms, namely the carbon atom of the -CH- group and, when R1- and OH R are different groups, the carbon atom to which these groups 30 are attached.
The compounds according to the invention thus include all enantiomers, diastereoisomers and mixtures thereof, including racemates. Compounds in which the carbon atom in the -CH- group is in the R configuration are preferred.
OH In the general formula (I), the chain "(CH2^m~ ma^ be, for example, - (CH2) 3-, (CH2)4"» -(CH2)5-, -(CH2)g- or -(CH2)y-f and the chain "(CH2^n" ma^ for example, -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5- or (CH2)g-.
Preferably the sum total of the number of carbon atoms in the chains - (Ci^)m- and "(CH2)n is 6 to 12 inclusive and may be, for example, 7, 8, 9 or 10.
Compounds wherein the sum total of m + n is 7, 8 or 9, are particularly preferred.
Preferred compounds of general formula (I) are those wherein m is 3 and n is 6, or m is 4 and n is 3, 4 or 5, or m is 5 and n is 2, 3, 4 or 5, or m is 6 and n is 2 or 3. 2 R and R , for example, may each be methyl, ethyl, propyl, or isopropyl groups except that if one of R1 2 and R is a propyl or isopropyl group, the other is a hydrogen atom or a methyl group. Thus, for example, R1 may be a hydrogen atom or a methyl, ethyl or propyl 2 group. R , for example, may be a hydrogen atom or a methyl group. 2 R and R are each preferably a hydrogen atom or a methyl group.
A preferred group of compounds is that wherein R1 and R are both hydrogen atoms. In another preferred 2 group of compounds R is a hydrogen atom and R is a C, - alkyl group, particularly a methyl group. In A J 12 yet another preferred group of compounds R and R are both methyl groups.
R1 l The chain -C(CH2)m0(CH2)n- in general formula (I) ’ 2 RZ may be, for example -(CH2)40(CH2)4~, (CH2)50(CH2)2~ -(CH2)50(CH2)3, -(CH2)50(CH2)4-, -CH(CH2)40(CH2)3-, CH-, CH, CH, I 3 I 3 | 3 -CH(CH2)40(CH2)4-, -CH(CH2)50(CH2)3, -CH(CH2)50(CH2)4-, CH- R11 3 I 1 -C(CH2)50(CH2)2", or -CH(CH2)50(CH2)2-, where RA is ch3 methyl, ethyl or propyl.
Examples of the optional substituents which may be present on the phenyl group represented by Ar include bromine, iodine or, in particular, chlorine or fluorine atoms, or methyl, ethyl, methoxy or ethoxy groups. In general, Ar is preferably an unsubstituted phenyl group. According to another preference, Ar is a phenyl group substituted by one substituent, particularly a fluorine or chlorine atom or a methoxy or methyl group.
Suitable physiologically acceptable salts of the compounds of general formula (I) include acid addition salts derived from inorganic and organic acids, such as hydrochlorides, hydrobromides, sulphates, phosphates, maleates, tartrates, citrates, benzoates, 4-methoxybenzoates, 2- or 4-hydroxybenzoates, 4-chlorobenzoates, p-toluenesulphonates, methanesulphonates, ascorbates, salicylates, acetates, fumarates, succinates, lactates, glutarates, gluconates, tricarballylates, hydroxynaphthalenecarboxylates e.g. 1-hydroxy- or 3-hydroxy-2naphthalenecarboxylates, or oleates. The compounds may also form salts with suitable bases. Examples of such salts are alkali metal (e.g. sodium and potassium), and alkaline earth metal (e.g. calcium and magnesium) salts.
The compounds according to the invention have a selective stimulant action at ^-adrenoreceptors, which furthermore is of a particularly advantageous profile.
The stimulant action was demonstrated in the guinea-pig, where compounds were shown to cause relaxation of PGF2a-contracted isolated trachea. In another test, compounds of the invention were shown to afford protection against, histamine-induced broncho-constriction when administered by inhalation or by an oral route in conscious guinea-pigs. In both tests, compounds according the invention have shown a particularly long duration of action. The selective action of compounds of the invention was demonstrated in the rat or guineapig where compounds were shown to have little or no effect on isolated rat or guinea-pig left atria (Bj-adrenoreceptor tissues) at concentrations where they cause relaxation of PGF2a" contracted isolated trachea. Compounds according to the invention have also been shown to inhibit the anaphylactic release of spasmagens and inflammagens from sensitised human tissues e.g. lung fragments.
The compounds according to the invention may be used in the treatment of diseases associated with reversible airways obstruction such as asthma and chronic bronchitis.
The compounds according to the invention may also be used for the treatment of premature labour, depression and congestive heart failure, and are also indicated as useful for the treatment of inflammatory and allergic skin diseases, psoriasis, proliferative skin diseases, glaucoma, and in the treatment of conditions in which there is an advantage in lowering gastric acidity, particularly in gastric and peptic ulceration. Λ particularly important group of compounds by virtue of the advantageously long duration of action they have shown in our tests, has the formula (Ia): r R CHCH-NHC(CH-) -0-(CH-) Ar I 2 ι 2 m 2 n OH R2 '/f (Ia) w. in which 12 R and R are as defined for general formula (I); m is an integer from 3 to 6, n is an integer from 2 to 6, and Ar is phenyl or phenyl substituted by a methoxy or methyl group, or more preferably a fluorine or chlorine atom, and the physiologically acceptable salts and solvates thereof, in each instance the sum total of carbon atoms in the chains "(CH2^m~ and ~^CH2^n" k®in9 an integer from 7 to 10 inclusive, in particular 7, 8 or 9.
A preferred group of compounds of formula (Ia) is 1 2 that wherein R and R is each a hydrogen atom.
In another preferred group of compounds of formula 2 (Ia) R is a hydrogen atom or a methyl group and R is a methyl group.
In a further group of compounds of formula (Ia) R^ and R each is a hydrogen atom and Ar is phenyl or phenyl 20 substituted by a methoxy group, or more preferably a fluorine or chlorine atom.
A particularly preferred group of compounds has the 1 2 formula (Ia) in which R and R each is a hydrogen atom or a methyl group, m is 4 or 5, n is 2, 3 or 4, and Ar is phenyl or phenyl substituted by a chlorine or fluorine atom or a methoxy or methyl group and the physiologically acceptable salts and solvates thereof.
Particularly important compounds are: 4-hydroxy-c?'[[ [6-(4-phenylbutoxy) hexyl] amino] methyl] -1,3-benzenedimethanol; and the physiologically acceptable salts thereof; 4-hydroxy-α1[[[6-(3-phenylpropoxy)hexyl]amino]methyl]-1,3-benzenedimethanol; and the physiologically acceptable salts thereof; 4-hydroxy-α1-[[[6-(2-phenylethoxy)hexyl]amino]methyl] -1,3-benzenedimethanol; and the physiologically acceptable salts thereof; 4-hydroxy-a1-[[[5-(4-phenylbutoxy)pentyl]amino]methyl]-1,3-benzenedimethanol; and the physiologically acceptable salts thereof; 4-hydroxy-a1-[[[l-methyl-6-(2-phenylethoxy)hexyl]a mino]methyl]-1,3-benzenedimethanol; and the physiologically acceptable salts thereof; 4-hydroxy-a1-[[[l-methyl-5-(3-phenylpropoxy)pentyl]amino]methyl]-1,3-benzenedimethanol; and the physiologically acceptable salts thereof; 4-hydroxy-a1- [ [ [ 1-methy1-5- (4-phenylbutoxy) pentyl] ?amino]methyl]-1,3-benzenedimethanol;and the physiologically acceptable salts thereof; 4-hydroxy-a1-[[[1-ethy1-6-(2-phenylethoxy)hexyl]amino]methyl]-1,3-benzenedimethanol; and the physiologically acceptable salts thereof; <χ!-[ [ [1,1-d ime t.hyl-6- (2-phenylethoxy) hexyl] amino] methyl-4-hydroxy-l,3-benzenedimethanol; and the physiologically acceptable salts thereof; a1-[[[6-[2-(4-fluorophenyl)ethoxy]-1-methylhexyl]aminojmethyl]-4-hydroxy-l,3-benzenedimethanol; and the physiologically acceptable salts thereof; 4-hydroxy-a1-[[[6-[3-(4-methoxyphenyl) propoxy]-1methylhexyl]amino]methyl]-1,3-benzenedimethanol;and the physiologically acceptable salts thereof; 4-hydroxy-a1-[[[l-methyl-6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol;and the physiologically acceptable salts thereof; 4-hydroxy-a1-[[[6-[2-(4-methylpheny1) ethoxy]hexyl]aminojmethyl]-1,3-benzenedimethanol; and the physiologically acceptable salts thereof; β1-[ [ [ 6-[2-(3-chlorophenyl) ethoxy]hexyl]amino]methyl] -4-hydroxy-l ,3-benzenedimethanol; and the physiologically acceptable salts thereof; 4-hydroxy-a^-[[[6-[2-(4-methoxyphenyl)ethoxy]hexyl]5 amino]-methyl]-1,3-benzenedimethanol; and the physiologically acceptable salts thereof; a[[[6-[3-(4-fluorophenyl) propoxy]hexyl]amino]methyl]-4-hydroxy-l,3-benzenedimethanol; and the physiologically acceptable salts thereof.
The compounds according to the invention may be formulated for administration in any convenient way.
The invention therefore includes within its scope pharmaceutical compositions comprising at least one compound of formula (1) or a physiologically acceptable v salt or solvate thereof formulated for use in human or veterinary medicine. Such compositions may be presented for use with physiologically acceptable carriers or excipients, optionally with supplementary medicinal agents.
The compounds may be formulated in a form suitable for administration by inhalation or insufflation, or for oral, buccal, parental, topical (including nasal) or rectal administration. Administration by inhalation or insufflation is preferred.
For administration by inhalation the compounds according to the invention are conveniently delivered in the form of an aerosol spray presentation from pressurised packs, with the use of a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide cr other suitable gas, or from a nebuliser. In the case of a pressurised aerosol the dosage unit may be determined by providing a valve to deliver a metered amount. tl Alternatively, for administration by inhalation or insufflation, the compounds according to the invention may take the form of a dry powder composition, for example a powder mix of the compound and a suitable powder base such as lactose or starch. The powder composition may be presented in unit dosage form in, for example, capsules or cartridges of e.g. gelatin, or blister packs from which the powder may be administered with the aid of an inhaler or insufflator.
For oral administration, the pharmaceutical composition may take the form of, for example, tablets, capsules, powders, solutions, syrups or suspensions prepared by conventional means with acceptable excipients.
For buccal administration the composition may take the form of tablets, drops or lozenges formulated in conventional manner.
The compounds of the invention may be formulated for parenteral administration. Formulations for injections may be presented in unit dosage form in ampoules, or in multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or agueous vehicles, and may contain formulatory agents such as suspending, stabilising and/or dispersing agents. Alternatively, the active ingredient may be in powder form for reconstitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.
For topical administration the pharmaceutical composition may take the form of ointments, lotions or creams formulated in a conventional manner, with for example an agueous or oily base, generally with the addition of suitable thickening agents and/or solvents.
For nasal application, the composition may take the form of a spray, formulated for example as an agueous solution or suspension or as an aerosol with the use of / / a suitable propellant.
The compounds of the invention may also be formulated in rectal compositions such as suppositories or retention enemas, e.g. containing conventional suppository bases such as cocoa butter or other glyceride.
Where pharmaceutical compositions are described above for oral, buccal, rectal or topical administration, these may be presented in a conventional manner associated with controlled release forms.
A proposed daily dosage of active compound for the treatment of man is 0.0005 mg to 100 mg, which may be conveniently administered in one or two doses. The precise dose employed will of course depend on the age and condition of the patient and on the route of administration. Thus a suitable dose for administration by inhalation is 0.0005 mg to 10 mg, for oral administration is 0.02 mg to 100 mg, and for parenteral administration is 0.001 mg to 2 mg.
The compounds according to the invention may be prepared by a number of processes, as described in the 1 2 following wherein m, n, Ar, R and R are as defined for general formula (I) unless otherwise specified.
In the general processes (1) to (3) described below the final step in the reaction may be the removal of a protecting group. Suitable protecting groups and their removal are described in general process (4) below.
According to one general process (1), a compound of general formula (I) may be prepared by alkylation. Conventional alkylation procedures may be used.
Thus, for example, in one process (a), a compound of general formula (I) in which R^ is a hydrogen atom may be prepared by alkylation of an amine of general formula (II): (II) 6 (wherein R , R and R each is a hydrogen atom or a protecting group and R is a hydrogen atom) followed by removal of any protecting group where present.
The alkylating reaction (a) may be effected using an alkylating agent of general formula (III) : LCH(CH2)m0(CH2)nAr 12 (III) (wherein L represents a leaving group, for example a halogen atom such as chlorine, bromine or iodine, or a hydrocarbylsulphonyloxy group such as methanesulphonyloxy or £-toluenesulphonyloxy).
The alkylation is preferably effected in the presence of a suitable acid scavenger, for example, inorganic bases such as sodium or potassium carbonate, organic bases such as triethylamine, diisopropylethylamine or pyridine, or alkylene oxides such as ethylene oxide or propylene oxide. The reaction is conveniently effected in a solvent such as acetonitrile or an ether e.g. tetrahydrofuran or dioxan, a ketone e.g. butanone or methyl isobutyl ketone, a substituted amide e.g. dimethylformamide or a chlorinated hydrocarbon e.g. chloroform at a temperature between ambient and the reflux temperature of the solvent.
According to another example (b) of an alkylation process, a compound of general formula (I) in which R1 represents a hydrogen atom may be prepared by alkylation of an amine of general formula (II), as previously defined 4 except that R is a hydrogen atom or a group convertible thereto under the reaction conditions, with a compound of general formula (IV); R2CO(CH2)m-0-(CH2)nAr (IV) in the presence of a reducing agent, followed when necessary by removal of any protecting groups.
Examples of suitable groups represented by R which are convertible into a hydrogen atom are arylmethyl groups such as benzyl, α-methyl benzyl and benzhydryl.
Suitable reducing agents include hydrogen in the presence of a metal catalyst such as platinum, platinum oxide, palladium, Raney nickel or rhodium, on a support, such as charcoal, using an alcohol, e.g. ethanol or an ester e.g. ethyl acetate or an ether e.g. tetrahydrofuran, or water, as reaction solvent, or a mixture of solvents, e.g. a mixture of two or more of those just described, at normal or elevated temperature and pressure, for example from 20 to 100°C and from 1 to 10 atmospheres. 4 Alternatively when one or both of R and R are hydrogen atoms, the reducing agent may be a hydride such as1diborane or a metal hydride such as sodium borohydride, sodium cyanoborohydride or lithium aluminium hydride. Suitable solvents for the reaction with these reducing agents will depend on the particular hydride used, but will include alcohols such as methanol or ethanol, or ethers such as diethyl ether or tert-butyl methyl ether, or tetrahydrofuran. 4 When a compound of formula (II) wherein R and R are both hydrogen atoms is used, the intermediate imine of formula (V) may be formed: chch2n=c(CH2) -0-(CH2)nAr I I ο OH κ (V) (wherein R6 and R3 are as defined for formula (II)).
Reduction of the imine using the conditions described above, followed, where necessary, by removal of any protecting groups, gives a compound of general formula (I).
Where it is desired to use a protected intermediate of general formula (II) it is particularly convenient to use hydrogen and a metal catalyst 3 5 as described above with protecting groups R , R and R6 which are capable of being converted to a hydrogen atom under these reducing conditions, thus avoiding the need for a separate deprotection step. Suitable protecting groups of this type include arylmethyl groups such as benzyl, benzhydryl and a-methylbenzyl.
In a second general process (2), a compound of general formula (I) may be prepared by reduction.
Thus, for example,a compound of general formula (I) may be prepared by reducing an intermediate of general formula (VI): X1-X2-X3-CH20CH2X-Ar (VI) c (wherein R is as defined for general formula (II) and at 12 3 4 least one of X, X , X , X and X represents a reducible group and the other(s) take the appropriate meaning as follows, which is X is CHjOR6, X1 is -CH(OH)-, X2 is -CH2NR3, X3 is -CR1R2(CH2)-_1 and X4 is -(CH2)-_]) followed where necessary by removal of any protecting groups.
Suitable reducible groups include those wherein 7 7 X is a group -CO-R (wherein R represents a hydrogen z 1 atom, or an alkyl, aryl or aralkyl group) or -CHO, X is a group -C=0, X is a group -CH2NY- (wherein Y represents a group convertible to hydrogen by catalytic hydrogenation, for example an arylmethyl group such as benzyl, benzhydryl or α-methylbenzyl), or an imine (-CH«N") group or a group -CONII-, and X3 is a group -CO(CH,)- ., or a group -CR^R2X^ where X$ is C2_7alkenylene or C2_7alkynylene, or X -X - is a group -CH2N=CR2(CH2) χ, and X4 is C2_galkenylene or C2_6alkynylene. In one convenient aspect of the reduction process, the group R may be a group convertible to hydrogen under the reducing conditions employed and may be for example an arylmethyl group such as benzyl, benzhydryl or α-methylbenzyl.
The reduction may be effected using reducing agents conveniently employed for the reduction of carboxylic acids, aldehydes, esters, ketones, imines, amides, ethylenes, acetylenes and protected amines. Thus, for example, when X in general formula (VI) represents a group -COjR or -CHO this may be reduced to a group -CHjOH using a hydride such as diborane or a complex metal hydride such as lithium aluminium hydride, sodium bis(2-methoxyethoxy)aluminium hydride, sodium borohydride, diisobutylaluminium hydride or lithium triethylborohydride in a solvent such as an ether, e.g. tetrahydrofuran or diethyl ether, or a 5 halogenated hydrocarbon e.g. dichloromethane at a temperature from 0°C to the reflux. Λ When X^ in general formula (VI) represents a -C=0 group this may be reduced to a -CH(OH)- group using hydrogen in the presence of a metal catalyst 10 as previously described for process (1) part (b). Alternatively, the reducing agent may be, for example, a hydride such as diborane or a metal .hydride such as lithium aluminium hydride, sodium bis(2-methoxyethoxy) aluminium hydride, sodium borohydride or aluminium 15 hydride. The reaction may be effected in a solvent, where appropriate an alcohol e.g. methanol or ethanol, or an ether such as tetrahydrofuran, or a halogenated hydrocarbon such as dichloromethane. 2 When X in general formula (VI) represents a 20 CH2NY group or the group -CH=N-, or -X -XJ represents -CH2N=CR2 (CHo^m-l this may be reduced to a -CHjNH- or -CIIjNHCHR2 (CH2)m_i group using hydrogen in the presence of a metal catalyst as previously described 2 for process (1) part (b). Alternatively, when X 25 * or -X2-X3 is the group -CII-N- or -CH2N=CR2 (CHj) χ this may be reduced to a-CH2NH-or CH2NHCHP2 (CH2)m_^ group using a reducing agent and conditions as just described for the reduction of X^ when this represents a -C=O group. 30 2 3 When X or X in general formula (VI) represents a -CONH- or "CO(CH2)-_^ 9rouP this may be reduced to a group -CH2NH- or -CH2(CH2)-_^ usin When X in general formula (VI) represents a group -CR1R2X5- this may be reduced to a group —CR^R^(CH2) using hydrogen in the presence of a catalyst such as platinum or palladium on a support such as charcoal * in a solvent such as an alcohol, e.g. ethanol or methanol, or an ester, e.g. ethyl acetate, or an ether, e.g. v tetrahydrofuran, at normal or elevated temperature and pressure.
When X is C2_galkenylene or C2_galkynylene this may be reduced to "(CIi2^n-l usin9 hydrogen and a catalyst as just described. In this aspect of the reduction process, suitable starting materials of formula (VI) include 12 5 4 those in which CR R X and/or X each contains one -C=Cor -CaC- linkage. Where both contain unsaturated linkages, these may be the same or different.
Particular examples of the reduction process are those in which a compound of general formula (I) in which "(CH2)m" represents -(CH2)g- is prepared from a corresponding compound in which "(CH2)m" represents -ch=ch(Ch2)3, -c=c(ch2)3-, -('ch2)2ch=chch2- or -(CH2)2C=CCH2~. In further examples, a compound of general formula (I) in which "(CH2^n~ rePresents -(CH2)j or -(CH2)3- may be prepared by reduction of a corresponding compound of general formula (I) in which ‘’(CII2^n* represents -CH2CH=CH-CH2, -CH2C=CCH2, -CH2CH2CH=CH-, -CH2CH2CaC-, -CH2CH=CH or -CHjCbC-.
In the reduction processes just described the 5 groups X and R in a compound of formula (VI) may r together conveniently represent a group R. OCH-- (where r9X 9 R and R , which may be the same or different, each represents a hydrogen atom or an alkyl or aryl group. After the reduction is complete, cleavage of this group using e.g. a dilute acid in a solvent such as water at normal temperature yields a compound of formula (I).
According to a further general process (3), a compound of general formula (I) may be obtained by reaction of a compound of general formula (VII): (VII) (wherein Z represents a group -CH - CH~ or -CHCH~L, \ / L OH and e £ L, R and R are as previously defined, with an amine of general formula (VIII): Y NHC(CH2)m-0-(CH2)n-Ar .2 (VIII) (wherein Y1 is a hydrogen atom or a group convertible thereto by catalytic hydrogenation) followed by removal of any protecting groups where present, as described hereinafter.
Suitable Y1 groups convertible into a hydrogen atom include arylmethyl groups such as benzyl, benzhydryl or a-methylbenzyl.
The reaction may be effected in the presence of a suitable solvent for example an alcohol, such as ethanol, a halogenated hydrocarbon e.g. chloroform, a substituted amide e.g. dimethylformamide or an ether such as tetrahydrofuran or dioxan at a temperature from ambient to the reflux, optionally in the presence of a base such as an organic amine e.g. diisopropylethylamine or an inorganic base such as sodium carbonate.
The intermediate amines of general formula (VIII) and their acid addition salts are novel compounds and form the subject of our U.K. Patent Publication 2 176 476 A. A particularly preferred group of amines of general formula (VIII) are those in which the total number of carbon atoms in the groups represented by C(CH-)_ and (CH9) is from 7 to 13 inclusive.
I ·· Hl £» «1 In another general process (4), a compound of general formula (I) may be obtained by deprotection of a protected intermediate of general formula (IX): 6 (wherein R , R and R are as previously defined 3 5 6 except that at least one of R , R and R is a protecting group).
The protecting group may be any conventional protecting group, for example as described in Protective Groups in Organic Chemistry, Ed. J.F.W. McOmie (Plenum Press, 1973). Examples of suitable hydroxyl protecting groups represented by R^ and R® are aralkyl groups such as benzyl, diphenyImethyl or triphenyImethyl, and tetrahydropyranyl. Examples of suitable amino protecting groups represented by R3 are aralkyl groups such as benzyl, α-methylbenzyl, diphenyImethyl or triphenyImethyl and acyl groups such as trichloroacetyl or trifluoroacetyl.
The deprotection to yield a compound of general formula (I) may be effected using conventional techniques. 6 3 Thus, for example, when R , R and/or R is an aralkyl group this may be cleaved by hydrogenolysis in the presence of a metal catalyst (e.g. palladium on charcoal).
When R5 and/or R6 is tetrahydropyranyl this may be cleaved by hydrolysis under acidic conditions. Acyl 3 groups represented by R may be removed by hydrolysis, for example with a base such as sodium hydroxide, or a group such as trichloroacetyl, or trifluoroacetyl may be removed by reduction with, for example, zinc and acetic acid.
In a particular embodiment of the deprotection process (4), R3 and R® may together represent a protecting group as in a compound of general formula (X): 9 (wherein R and R are as previously defined).
A compound of general formula (I) may be obtained by treatment of a compound of formula (X) with a dilute acid, for example hydrochloric acid in a solvent such as water or an alcohol such as ethanol at normal or elevated temperature.
In the general processes (1) to (4) described above, the compound of formula (I) obtained may be in the form of a salt, conveniently in the form of a physiologically acceptable salt. Where desired such salts may be converted to the corresponding free base using conventional methods.
Physiologically acceptable salts of the compounds of general formula (I) may be prepared by reacting a compound of general formula (I) with an appropriate acid or base in the presence of a suitable solvent such as acetonitrile, acetone, chloroform, ethyl acetate or an alcohol e.g. methanol, ethanol or iso-propanol.
Physiologically acceptable salts may also be prepared from other salts, including other physiologically acceptable salts, of the compounds of general formula (I), using conventional methods.
When a specific enantiomer of a compound of general formula (I) possessing one asymmetric carhon atom is required# this may be obtained by resolution of a mixture of enantiomers of a corresponding compound of general formula (I) using conventional methods.
Thus, in one example an appropriate optically active acid may be used to form salts with a mixture of enantiomers of a compound of general formula (I).
The resulting mixture of isomeric salts may be separated# for example by fractional crystallisation# into the diastereoisomeric salts from which the required enantiomer of a compound of general formula (I) may be isolated by conversion into the required free base.
Alternatively# enantiomers of a compound of general formula (I) possessing one asymmetric carbon atom may be synthesised from the appropriate optically active intermediates using any of the general processes described herein.
When a compound of formula (I) contains two asymmetric carbon atoms# specific diasteroisomers or enantiomers thereof may be obtained from an appropriate asymmetric starting material or by separation of an appropriate mixture of isomers using techniques just described.
Suitable methods for preparing the intermediate compounds used in the above general processes are described below. In the following discussion, Ar# m# n# R1, R2, R3 , R4, Y and Υ1, Ζ, X, X1, X2, X3 and L are as defined above except where otherwise indicated.
Hal represents a halogen atom. Where an intermediate with protected hydroxyl and/or amino groups is desired# this may be obtained using conventional protection methods# for example those described by McOmie (see process (4) above).
The intermediate compounds of general formula (III) may be prepared by reaction of an alcohol of general formula (XI): Ar(CH2)nOH (XI) with a disubstituted alkane of general formula (XII): LCH2(CH2) L1 (XII) (wherein L1 is as previously defined for L, and L and L1 may be the same or different), optionally in a solvent such as tetrahydrofuran or dimethylformamide at a 10 temperature up to the boiling point. The reaction is effected by first generating the anion of the alcohol of general formula (XI) by adding for example sodium, sodium hydride or a strong base such as sodium hydroxide and a phase transfer catalyst such as tetrabutylammonium 15 sulphate. Optionally a solvent such as dichloromethane or tetrahydrofuran may be added. The reaction can be carried out at ambient or elevated temperatures.
The compounds of general formulae (XI) and (XII) are either known compounds or they may be made by methods analogous to those used for the preparation of the known compounds.
Intermediate aldehydes of general formula (IV) (in which R represents a hydrogen atom) may be prepared by oxidation of an alcohol of general formula (XIII): Ar(CH2)n0(CH2)mCH2OH (XIII) with an oxidising agent such as pyridinium chlorochromate in a solvent such as a halogenated hydrocarbon, e.g. dichloromethane. The alcohols of formula (XIII) may be prepared from the compounds of formula (III), for example by reaction with sodium acetate, followed by hydrolysis of the product with for example sodium hydroxide.
Intermediate ketones of formula (IV) (in which R represents an alkyl group), may be prepared by reaction of a Grignard complex of a halide of formula (XIV): Ar(CH2)n0(CH2)mHal (XIV) 2 with an acyl halide R COCI or anhydride (R CO)20 in a solvent such as an ether, for example diethyl ether or tetrahydrofuran. The halides of formula (XIV) may be prepared by alkylation of an alcohol of formula (XI) with a disubstituted alkane of formula L(CH2)mHal as described above for the preparation of compounds of formula (III). Compounds L(CH2)mHal are either known compounds or they may be made by methods analogous to those used for preparation of the known compounds.
Intermediate compounds of general formula (VI) for use in general process (2) may be prepared by a number of processes.
Thus for example intermediates of general formula (VI) in which X3 is a group -C=0 may be prepared from a haloketone of formula (XV): (XV) by reaction with an amine of general formula (VIII). The reaction may be effected in a cold or hot solvent, for example tetrahydrofuran, tert-butyl methyl ether, dioxan, chloroform, dimethylformamide, acetonitrile or a ketone such as butanone or methylisobutyIketone, • ·* or an ester, for example ethyl acetate preferably in the presence of a base such as diisopropylethylamine, sodium carbonate or other acid scavenger such as propylene oxide. When "(CH2^m an^/°r "^CII2^n amine of formula (VIII) contains an unsaturated linkage, an intermediate of formula (VI) in which X 12 5 4 is -CR R X - and/or X is C2-galkenylene or C2-6 alkynylene may be obtained in this process.
Intermediates of general formula (VI) in which X^ is a group -C=0 may be reduced to the corresponding intermediate in which X^ is a group -CH(OH)- using for example a metal hydride such as sodium borohydride in a solvent e.g. ethanol.
Iminoketones of general formula (VI) i.e. in 2 which X is a group -CH-N- may be obtained from a phenylglyoxal derivative of formula (XVI): X COCHO (XVI) by reaction with an amine of formula (VIII) in which yl represents a hydrogen atonv in a solvent such as benzene, tetrahydrofuran or an alcohol e.g. ethanol at temperatures up to the reflux. The phenylglyoxal derivatives of formula (XVI) may be obtained from a haloketone of formula (XV) by the action of a dialkylsulphoxide such as dimethylsulphoxide.
When X and R5 in the glyoxal of formula (XVI) o together represent a group R® /OCH_- the iminoketone R9X of formula (VI) so formed using this process subsequently may be reduced using a metal hydride such as sodium borohydride in a solvent such as ethanol to yield a compound of formula (X).
Intermediates of general formula (VI) in which X3 is a group -CO(CH2)m" may be prepared by acylation of an amine of formula (XVII): X using an ester or an activated derivative of an acid of formula (XVIII): Ar(CH2)n0(CII2)mCO2H (XVIII) Suitable activated derivatives include the acid chloride, an anhydride or imidazolide. The reaction may be optionally carried out in a solvent such as tetrahydrofuran, benzene or chloroform, optionally in the presence of a base such as pyridine or triethylamine. The acids (XVIII) may be used directly if a coupling agent such as dicyclohexylcarbodiimide is added.
Acids of formula (XVIII) may be obtained by treatment of an alcohol of general formula (XIII) with a suitable oxidising agent, for examle pyridinium dichromate in a solvent such as dimethylformamide. 3 Intermediates of formula (VI) in which -X -X 2 represents -CH2N=CR may be obtained by reaction of an amine Of formula (XVII) in which R3 is a hydrogen atom with a compound of formula (IV) in a solvent such as acetonitrile.
Intermediates of formula (VI) in which X is -CONH- may be prepared by reaction of an amine of formula (VIII) with an acid of formula (XIX) X (XIX) 7 in the presence of a coupling agent such as dicyclohexylcarbod iimide .
Compounds of formula (VII) in which Z represents a group -CHCH.Hal may be prepared from a haloketone ι z OH of formula (XX): by reduction using for example a metal hydride such as sodium borohydride in a solvent such as ethanol.
The halogen atom may be displaced to yield other compounds of general formula (VII) in which Z is a uroup -CHCH,L where L is a leavina qroup· other ' . Ah than a halogen atom.
Compounds of formula (VII) wherein Z represents -CH - CH2 may be prepared from the corresponding compound in which Z is CHCH-L by treatment with a base , for example I z OH an amine, which may be for example a compound of general formula (VIII), or an inorganic base such as sodium hydroxide in a solvent such as ethanol.
The amines of general formula fVIII) in which 12 Y is a group convertible to hydrogen and F and F are both hydrogen atoms may be prepared by reaction 2 of a compound of general formula (III) in which R is a hydrogen atom with an amine Y'NHj· The reaction may be effected in the absence or presence of a solvent such as a ketone e.g. butanone or methyl isobutyl ketone, an ether e.g. tetrahydrofuran or a substituted amide e.g. dimethylformamide, optionally in the presence of a base such as sodium carbonate or an organic amine e.g. triethylamine or N,N-diisopropylethylamine at temperatures between 0°C and the reflux. Where desired, subsequent reaction with hydrogen in the presence of a metal catalyst such as platinum in a solvent such as an alcohol e.g. ethanol yields a compound of 1 ! formula (VIII) where Y is a hydrogen atom.
Alternatively, amines of formula (VIII) in which R1 is a hydrogen atom may be prepared by reductive alkylation of an amine Y^NHj, in which Y^ is a group convertible into hydrogen with a compound of formula (IV), if necessary followed by conversion of the Y1 group to a hydrogen atom as just described.
The reaction may be effected by hydrogen in the absence or presence of a solvent such as an alcohol, e.g. ethanol with a metal catalyst such as platinum or palladium, or by use of a complex metal hydride such as sodium borohydride or sodium cyanoborohydride in an alcohol, for example, ethanol.
A process to afford amines of formula (VIII) in 1 2 which R and R can both be alkyl groups uses an acid of formula (XXI): R1 I HO2CC(CH2)m0(CH2)nAr (XXI) The acid is converted via its chloride and azide by a Curtius reaction into the amine of formula (VIII) in which γ* is a hydrogen atom. The reaction involves thermal rearrangement of the azide into an isocyanate, which is hydrolysed by treatment with an inorganic base, for example aqueous sodium hydroxide optionally in a solvent such as ethanol.
The acids of formula (XXI) can be prepared by alkylation of the acid (XXII): CHCO2H (XXII) via its dilithio derivative with an alkylating agent' of formula (XIV) in a solvent such as an ether, for example tetrahydrofuran at low temperature such as 0°C to ambient.
The compounds of formulae (II), (IV), (XVII), (XIX), (XX), (XXI) and (XXII) are either known compounds or may be obtained by analogous methods to those used for the preparation of the known compounds.
The following examples illustrate the invention.
Temperatures are in °C. Thin layer chromatography (T.l.c.) was carried out - pvfer-ZSiOj and 'dried' refers to drying using magnesium sulphate, except where otherwise stated.
The following abbreviations are used: DMF - dimethylformamide; THF tetrahydrofuran; EA - ethyl acetate; ER - diethyl ether; CX cyclohexane; HX - hexane; BR - brine; flash column chromatography [FCS] - on silica [FCTS] - on triethylamine-deactivated silica; T.l.c.EN t.l.c. over triethylamine-deactivated S1O2.
Eluants used for chromatography and t.l.c. are: [A] - CX-ER(19:1); [B] - CX-ER(9:1); [C] - ER-CX-triethylamine (60:40:1); ID] - CX-ER(1:4); [E] - CX-FA(19:1); [F] - CX-ER(4:1); [G] ER; [H] - EA; [I] - EA-methanol-triethylamine(9:1:0.1); [J] CX-ER(7:3); [K] - CX-EA(9:1); [L] - CX-ER (3:1); [M] EA-CH3OH-NH3(9:1:0.1),- [N] - EA-CH3OH(9:1); [O] - CX-ER(1:1).
Intermediate 1 is a*-( am inomethyl)-4-hydroxy-l,3- benzenedimethanol.
Intermediate 2 [2-[(6-Brcmohexyl)oxy]ethyl]benzene A mixture of phenethyl alcohol (20g), 1,6-dibrcmohexane (195g) and tetrabutylammonium bisulphate (3.0g) in 50% w/v NaOH solution (100ml) was heated at 65-70° for 4h. lhe cooled reaction mixture was poured into H20 (400ml) and extracted with CX (2x300ml). The dried extracts were evaporated in vacuo to give a yellow liquid which was purified by distillation under reduced pressure to give the title compound as a colourless liquid (26g) b.p. 110°/0.1mm. T.l.c. (EA) Rf 0.62.
Intermediate 3 [4-[(6-Brcmohexyl)oxy]butyl]benzene NaH (46% dispersion in oil; 6.5g) was added portionwise to a solution of 4-phenyl-1-butanol (15.0g) and 1,6-dibromohexane (48.8g) in THF (200ml) under nitrogen, lhe resulting suspension was refluxed for 27h and treated with H2O (80ml). lhe mixture was extracted with ER (2x200ml) and the dried extract was evaporated to leave an orange oil. The oil was purified on a column of silica (800ml) [A] to give a yellow oil which οί distillation gave the title ccmpound as a colourless oil (15.0g) b.p. 90-95°/0.1mmHg.
Intermediate 4 is a1-[[bis(phenylmethyl)amino]methyl]-4-hydroxy1,3-benzenedimethanol.
Intermediate 5 6-(4-Phenylbutoxy)hexan-l-ol A mixture of Intermediate 3 (lOg) sodium acetate trihydrate (34.8g), H2O (25ml) and trioctylpropyl NH4C1 (2g) was stirred vigorously on a steam bath for 2.5h. 2M NaOH (50ml) and ethanol (50ml) were added to the cooled mixture which was then stirred at RT for 30min. The mixture was diluted with BR (200ml), extracted with ER and the organic phase washed with H2O (200ml), BR (200ml), dried and evaporated under reduced pressure to give the title alcohol as a yellow oil, (7.16g).
T.l.c. [G] Rf 0.73.
Intermediate 6 6-(4-Phenylbutoxy)hexanal Pyridinium chlorochromate (4.1g) was added to a solution of Intermediate 5 (3g) in CH2C12 (25ml). The mixture was stirred at RT for 0.75h, triturated with ER (75ml), and filtered through Hyflo (Registered Mark). The filtrate was evaporated and the residue dissolved in ER (50ml), filtered through silica and evaporated under reduced pressure to give a pale yellow oil. Purification by [FCS] (120g) [B] gave the title conpound as a colourless oil (1.65g). T.l.c. [B] Rf 0.3.
Intermediate 7 N-[6-(4-Phenylbutoxy)hexyl]benzenemethananine A solution of benzylamine (16.64g) and Intermediate 3 (11.27g) in THF (45ml) was kept at RT for 4 days, diluted with ER (450ml), filtered and the filtrate evaporated to give a colourless oil which was purified by [PCS] [Cl to give the title compound (9.94g) as a colourless oil. Analysis Found: C,81.60;H,10.1;N,4.2. C23H33NO requires C,81.35;H,9.80;N,4.15%.
Intermediate 8 1-[4-Hydroxy-3-(hydroxymethyl)phenyl]-2-[6-(4-phenylbutoxy)hexyl] (phenylmethyl)amino]ethanone A solution of 2-bromo-l-[4-hydroxy-3-(hydroxymethyl)phenyl]ethanone (lg), Intermediate 7, (1.4g) and Ν,Ν-diisopropylethylamine (0.8g) in THF 3 (10ml) was kept at 23° for 3 days. The mixture was diluted with ER (60ml), washed with 8% NaH003 (50ml) and BR (50ml), dried and evaporated in vacuo to give an oil. Purification by (PCS] (40g) (D] afforded the title compound as a viscous yellow oil (1.68g).
T.l.c. [D] Rf 0.42.
Intermediate 9 2-Brono-1-(2,2-d imethyl-1,3-benzod iaxan-6-yl) ethanone 2-Methoxypropene (lOg) was added over 15min to a stirred solution of 2bramo-l-[4-hydroxy-3-(hydroxymethyl)phenyl]ethanone (5g) and toluene-4sulphonic acid (0.5g) in CH2C12 (100ml) at 23°. The mixture was stirred for 3h, filtered through a wad of triethylamine-deactivated silica and evaporated to give an oil. Purification by [FCTS] (300g) [E] afforded the title compound as an oil (4.8g) which solidified on cooling. A small sample was crystallised frcm light petroleum (b.p. 60-80°) to give white crystals m.p. 47-48°.
Intermediate 10 1-(2,2-Dimethyl-l, 3-benzod ioxan-6-yl )-2-(6-( 4-phenylbutoxy) hexyl ] (phenyImethyl)amino]ethanone A solution of Intermediate 9 (1.6g), Intermediate 7 (2.1g) and N,Wdiisopropylethylamine (1.2g) in THF (15ml) was kept at 23° for 2 days. The mixture was diluted with EA (80ml) washed with 8% NaHCO3 (50ml) and HR (50ml), dried (Na290u) and evaporated in vacuo to give a yellow oil. Purification by [PCS] (150g) [F] gave the title compound as a pale-yellcw oil (2.2g). T.l.c. (F] Rf 0.27.
Intermediate 11 6-(4-Phenylbutoxy)hexanoic acid A mixture of Intermediate 5 (4g) and pyridinium dichromate (21.04g) in DMF (50ml) was stirred at KT for 15h, diluted with H2O (300ml) and extracted with ER (2x100ml). The extract was washed with H2O (2x250ml), dried, filtered through a bed of silica and evaporated in vacuo to give a colourless oil. Purification by [FCS] (80g) [F] gave the title compound as a colourless oil (0.85g).
T.l.c. [F] Rf 0.27.
Intermediate 12 N- [2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl )-1-(4phenylbutoxy)hexananide DMF (0.003ml) and thionyl chloride (0.51ml) were added to a solution of Intermediate 11 (0.89g) in dry CH2C12 (17ml). The resultant solution was stirred at KT for 2.5h and evaporated to dryness to give the acid chloride. Intermediate 1 (0.934g) in THF was treated with ethyl (trimethylsilyl)acetate (3.57ml). Tetrabutyl ammonium fluoride (0.9ml) was added dropwise to the stirred suspension at 0°. lhe resulting solution was stirred at RT for 2h and added to a solution of the above acid chloride in THF (10ml) under an atmosphere of nitrogen. Triethylamine (3.4ml) was then added and the solution stirred at RT for 4h, left to stand overnight, added to 2N hydrochloric acid (30ml) and stirred for 15min. The product was extracted into EA (3x25ml) the extracts were washed with H2O (25ml), 8% NaH003 solution (25ml) and BR (25ml). The dried (Na23Ο^) organic layer was evaporated to dryness to give a brown oil which was chromatographed on silica (Merck art 7754, 40g) [H] to give a pale yellow oil. The dried oil solidified to give the title amide as an off white solid (1.06g), m.p. 96- 97.5°.
Intermediate 13 6-(4-Phenylbutoxy)hexanamine Intermediate 7 (25g) in absolute ethanol (250ml) was hydrogenated over palladium on carbon (lg) and platinum on carbon (lg) catalysts, lhe mixture was filtered through Hyflo and evaporated under reduced pressure to give the title amine as a colourless oil (16.49g).
T.l.c. EN(CH3OH) Rf 0.3.
Intermediate 14 Methyl 2-hydroxy-5-[([6-(4-phenylbutoxy)hexyl] imino]acetyl]benzoate A solution of Intermediate 13 (0.49g) in methanol (5ml) was added over 15 min to a stirred suspension of methyl 5-(dihydroxyacetyl)-2hydroxybenzoate in methanol (10ml) at 23°. The mixture was stirred for lOmin, evaporated in vacuo and the residue purified by [FCTS] (40g) [G] to give the title imine as a dark-orange oil (0„61g). The imine was unstable and should be used promptly after preparation.
T.l.c. EN[G] Rf 0.37.
Intermediate 15 g- (Branomethyl) -2,2-d imethy 1-4 H-l, 3-benzod ioxin-6-methanol NaBH^ (O.Ig) was added to a stirred solution of Intermediate 9 (0.6g) in ethanol (20ml) at 0°. The mixture was stirred at 0° for lh, diluted with H2O (50ml) and extracted with EA (2x25ml), lhe extract was washed with BR (25ml) dried and evaporated to give an oil which on trituration with HX afforded the title brcmohydrin as a white solid (0.55g) m.p. 84-85° unchanged on recrystallisation from HX.
Intermediate 16 2,2-Dimethyl-6-oxiranyl-4H-l,3-benzodioxin A mixture of Intermediate 15 (0.45g), methanol (10ml) and anhydrous K2CO3 (0.25g) was stirred at 23° for 2h. The mixture was diluted with ER (50ml) filtered through a small wad of silica and evaporated in vacuo, lhe residual oil was dissolved in ER (50ml), dried and evaporated to give the title epoxide as an oil (0.27g).
T.l.c. (CX-EA 7:3) Rf 0.56.
Intermediate 17 ί 4-(2-Propynyloxy)butyl]benzene A mixture of propargyl alcohol (10.Og), (4-brcmobutyl)benzene (38.Og), aqueous NaOH (80ml, 50% w/v), and tetrabutylammonium bisulphate (l.Og) was stirred vigorously for 3 days, treated with H2O (100ml) and extracted with ER (2x200ml). lhe dried extract was evaporated and the residue was purified on a column of silica (Merck (Registered Trade Mark) 9385; 500ml) [H] to give the title ccnpound as a colourless oil (18.3g). T.l.c. [A] Rf 0.2.
Intermediate 18 [[4-(6-Chloro-2-hexynyl)oxy]butyl]benzene Intermediate 17 (15.0g) was added dropwise to a suspension of lithamide from lithium (0.61g) in liquid ammonia (50ml) at -33°. lhe mixture was stirred for 2h and bromochloropropane (13.9g) in ER (10ml) was added dropwise. lhe resulting suspension was stirred at -33° for 3h and ammonia was allowed to evaporate overnight. The residue was treated cautiously with H2O (30ml) and extracted with ER (3x50ml). The dried extract was evaporated and the residue was distilled to give the title compound as a colourless oil (12.9g) b.p. 140-150°/0.3nuHg.
T.l.c. [A] Rf 0.2.
Intermediate 19 [[4-(6-Iodo-2-hexynyl)oxy]butyl]benzene A mixture of Intermediate 18 (12.0g) sodium iodide (20.0g), and butanone (50ml) was refluxed for 6h and stirred at RT for 2 days, filtered and evaporated. lhe residue was dissolved in ER (50ml) and washed with H2O (50ml) and aqueous sodium thiosulphate (50ml). lhe dried organic phase was evaporated to leave the title conpound as a pale yellow oil (12.6g).
Intermediate 20 4-Hydroxy-g1-([[6-(4-phenylbutoxy)-4-hexynyl]aminolmethyl )-1,3benzenedimethanol Intermediate 19 (8.66g) was added dropwise to a solution of Intermediate 1 (6.7g) and Ν,Ν-diisopropylethylamine (3.9g) in DMF (250ml) at 70°.
The mixture was heated at 70° for 2h and DMF was removed under reduced pressure. lhe residue was treated with aqueous NaHOO3 (1M; 200ml) and extracted with EA (3x250ml). The dried extract was evaporated and the residue was purified on a column of silica (Merck 9385; 250ml) [I] to give a yellow oil. Trituration of the oil with ER gave the title conpound as a white solid (4.3g), m.p. 89-90°.
T.l.c. [Ml Rf 0.2.
Intermediate 21 3— [ [ (6-Branohexyl)oxylpropylIbenzene 3-Phenylpropanol (3.00g) and 1,6-dibromohexane (16.10g, 10.2ml) were stirred rapidly at RT with tetra-n-butylanmonium hydrogen sulphate (0.5g) and 12.5M aqueous NaOH (16ml) for 3Oh. lhe mixture was diluted with H2O (80ml), extracted with ER (3x100ml), and the combined organic extracts were washed consecutively with H2O (80ml) and BR (80ml). lhe dried extracts were evaporated and the residual oil purified by (FCS), eluting with CX (one columnful), followed by EA-CX (1:20) to give the title compound (5.35g) as a colourless oil.
Analysis Found:C,60.25;H,7.8;Br,26.45.
C15H23BrO requires C,60.2;H,7.75;Br,26.7%.
Intermediate 22 N-[6-(3-Phenylpropoxy)hexyl1benzenemethanamine hydrobrcmide Intermediate 21 (317g) was added to benzylamine (1116ml) at a temperature of 115-125° with stirring under nitrogen. Excess benzylamine was removed by distillation under reduced pressure. The residue was treated with methyl isobutyl ketone (1280ml), the temperature adjusted to 50° and 47% w/v hydrobrcmic acid (115ml) in H2O (800ml) was added at 50-55°. The aqueous phase was removed and the organic solution was washed with H2O (3x800ml) at 50°. Distillation under reduced pressure and crystallisation of the residue from propan-2-ol afforded the title compound salt (318g), m.p. 135-136°.
Intermediate 23 Methyl 2-hydroxy-5-[[(phenyImethyl)(6-(3-phenylpropoxy)hexyl1 amino] acetyl]benzoate A solution of Ν,Ν-diisopropylethylamine (9.93g) in CH2C12 (15ml) was added to a solution of methyl 5-bromoacetyl-2- hydroxybenzoate (lOg) and Intermediate 22 (14.87g) in CH2C12 (256ml) at 16°. The solution was stirred under nitrogen for 23h at 20°, washed with H2O (5x100ml), dried and filtered. This solution of the title ccanpound was used without further purification. T.l.c. (ER) Rf 0.7.
Intermediate 24 1-(4-((6-Bramohexyl)oxy]butyl]-2-methoxybenzene NaH (46% dispersion in oil; 1.36g) was added portionwise to a solution of 2-methoxybenzenebutanol (5.0g) and 1,6-dibromohexane (13.8g) in THF (50ml). The suspension was refluxed for 20h and was treated cautiously with H2O (20ml). The resulting emulsion was extracted with ER (2x50ml) and the dried extract was evaporated to leave a yellow oil. The oil was purified on a column of silica (Merck 9385, 600ml) [A] to give the title compound as a colourless oil (5.6g). T.l.c. [B] Rf 0.2.
Intermediate 25 Benzenehexanol (3-Brcmopropyl)benzene (20g) in IHF (75ml) was added dropwise to magnesian (2.43g) at a rate to maintain gentle reflux. The mixture was stirred for 2h at RT and oxetane (lOg) was added dropwise. The resulting suspension was stirred at RT for 2h and at reflux for 16h and poured into saturated aqueous NH^Cl (100ml). The mixture was extracted with ER (3x75ml) and the dried extract was evaporated to leave a yellow oil. Distillation of the oil gave the title ccmpound as a colourless liquid (6.05g) b.p. 100-105°/0.4mmHg. T.l.c. [O] Rf 0.3.
Intermediate 26 2-[(4-Chlorobutyl)oxy]tetrahydropyran Dihydropyran (15.5g) was added dropwise to a mixture of 4-chlorobutanol (20g) and hydrochloric acid (18M, 1 drop) at RT. The mixture was stirred for 30min and washed with H20 (100ml), aqueous NaHC03 (IM, 50ml, and BR (50ml). The dried liquid was heated under reduced pressure to leave the title conpound as a colourless liquid (31.9g). T.l.c. [L] Rf 0.5.
Intermediate 27 2-[(4-[(6-Phenylhexyl)oxy]butyl]oxy]tetrahydropyran NaH (3.85g) was added portionwise to a mixture of Intermediate 25 (5.5g), Intermediate 26 (30g), potassium iodide (lg) and THF (50ml). lhe mixture was refluxed for 28h and treated cautiously with H2O (100ml). The resulting emulsion was extracted with ER (3x100ml) and the dried extract was evaporated to leave a yellow oil. Excess of Intermediate 26 was distilled from the mixture at 80°/0.4mnHg and the residue was purified on a column of silica (300ml) IB] to give the title compound as a colourless oil (2.7g). T.l.c. [B] Rf 0.25.
Intermediate 28 4-[(6-Phenylhexyl)oxy]butan-l-ol A solution of Intermediate 27 (2.65g) in methanol (20ml) and 80% acetic acid (10ml) was stirred at RT for 20h. The solution was basified with aqueous NaOH (2M). lhe mixture was refluxed for 2h and methanol was evaporated. The resulting emulsion was extracted with ER (2x50ml) and the dried extract was evaporated to leave the title ccmpound as a colourless oil (2.0g).T.l.c. [0] Rf 0.3.
Intermediate 29 4- [ (6-Phenylhexyl) oxy] butan-l-ol methanesulchonate Methanesulphonyl chloride (0.4g) was added dropwise to a solution of Intermediate 28 (0.8g, and triethylamine (0.5g) in CH2C12 (5ml) at 0°. lhe mixture was stirred at RT for 25min and filtered. The filtrate was washed with saturated aqueous NaH003 (20ml) and BR (20ml). The dried (Na29O4) organic phase was evaporated to leave the title compound as a yellow oil (l.Og).
Intermediate 30 2-[2-[(6-Bramohexyl)oxy]ethyl1-1, 3-d imethylbenzene NaH (46% dispersion in oil; 4.2g) was added portionwise to a solution of 2,6-dimethylbenzenethanol (6.0g) and 1,6-dibromohexane (19.52g) in THF (50ml) under nitrogen. The mixture was refluxed for 18h and treated cautiously with H2O (20ml). The resulting emulsion was extracted with ER (3x100ml) and the dried extract was evaporated to leave a yellow oil. Excess 1,6-dibrcmohexane was removed under reduced pressure and the residue was purified on a column of silica (300ml) [B] to give the title compound as a colourless oil (6.6g) b.p. 110-115°/0.4mmHg.
The following intermediates were prepared in a similar manner to Intermediate 21.
Intermediate 31 4- [[(6-Branohexyl)oxy]butyl]-1-methoxybenzene (3.3g), b.p. 180-190°/0.5 torr, frcm 1,6-dibrcmohexane (8g) and 4-(4-methoxyphenyl)butanol (2g).
Intermediate 32 - [ [ (5-Brcmopentyl)oxy]pentyl]benzene (3.2g), b.p. 185-195°/0.3 torr, frcm 1,5-dibromopentane (8.5g) and benzenepentanol (2g).
Intermediate 33 1-[2-[(6-Branohexyl)oxy]ethyl-4-chlorobenzene (4.0g), b.p. 169°/0.8 torr, frcm 1,6-dibrcmohexane (8,65g) and 4-chlorobenzeneethanol (3.0g).
Intermediate 34 1-[3-[(6-Brcmohexyl)axy]propyl]-4-fluorobenzene (2.22g), b.p. 170°/0.7 torr, frcm 1,6-dibrcmohexane (8.82g) and Intermediate 42 (2.0g).
Intermediate 35 [2-[(8-Brcmooctyl)oxy]ethyl]benzene (4.3g), T.l.c. [B] Rf 0.3, from 1,8-dibrcmooctane (13.4g) and benzeneethanol (20g) Intermediate 36 [5-(6-(Brcmohexyl)oxy]pentyl]benzene (2.7g), T.l.c. [B] Rf 0.3, from 1,6-dibrcmohexane (9.0g) and benzenepentanol (2.0g).
Intermediate 37 1-(2-((6-Brcmohexyl)oxy]ethyl]-4-ethylbenzene (2.6q), T.l.c. [Bl Rf 0.25, from 1,6-dibrcmohexane (9.8g) and 4- ethylbenzeneethanol (2.0g).
Intermediate 38 [3-((7-Branoheptyl)oxy]propyl]benzene (2.05g) from 1,7-dibramoheptane (3.83g) and 3-phenylpropanol (1.08ml).
Analysis Found: C,62.6;H,8.4.
C16H2bBrO re<3uires C,61.35;H,8.05%.
Intermediate 39 -[4-[(6-Brcmohexyl)oxy]butyl]-1,3-benzodioxolane (3.2g), T.l.c. (CX-EA 4:1) Rf 0.43, from 1,6-dibrcmohexane (9.5g) and Intermediate 44 (2.5g).
Intermediate 40 1-(2-((6-Brcmohexyl)oxy]ethyl]-3-chlorobenzene (4.12g), T.l.c. (ER- HX 1:79) Rf 0.16, from 1,6-dibrcmohexane (11.71g) and 3chlorobenzeneethanol (2.5g).
Intermediate 41 20 1-(3-((6-Brcmohexyl)oxy]propyl]-2-fluorobenzene (4.71g), T.l.c. (ER- (X 1:79) Rf 0.22, fran 1,6-dibromohexane (14.28g) and 3-(2fluorophenyl)-1-propanol (3.0g).
Intermediate 42 4-Fluorobenzenepropanol a Grignard reagent was prepared from 4-brcmo-l-fluorobenzene (8.0g), magnesium turnings (1.10g), and iodine (one small crystal) in THF (40ml). Oxetane (2.3g) in THF (10ml) was added at RT and the reaction mixture was heated at reflux overnight. The cooled solution was poured into aqueous saturated NHUC1 (100ml), extracted with ER (2x150ml) and 30 the combined, dried (NagSO^) extracts were evaporated. The residual oil was purified by flash chromatography over silica gel (Merck 9285, 5.0cm wide column), eluting with ER- CX (1:5*1:3). The resultant oil was further purified by distillation to give the title ccnpound (3.15g) as a colourless oil, b.p. 150°/0.8 torr.
Intermediate 43 (E/Z)-4-[1,3-Benzodioxol-5-yl]-3-butenol, (E:Z=3:2) A solution of n-butyllithium in HX (1.6M, 6.5ml) was added over 5min to a stirred suspension of (3-(1-methoxy-1-methylethoxy)propyl]triphenylphosphonium bromide (4.8g) in dry THF (25ml) at 0° under nitrogen. The mixture was stirred at 0° for 45min, treated with a solution of piperonal (1.2g) in dry THF (5ml) and stirred at 0° to 23° over lh. ER (70ml) was added, the mixture filtered through silica and the filtrate evaporated in vacuo to give a yellow oil which was dissolved in a mixture of THF-H2O-2M hydrochloric acid 25:5:1 (31ml) and kept at 23° for 0.5h. The mixture was diluted with 8% NaHC03 (30ml), extracted with ER (2x50ml) and the extract was washed with BR (50ml), dried and evaporated in vacuo to afford the title alcohol as a yellcw oil (1.05g) (E:Z ratio of 3:2). T.l.c. [O] Rf 0.22.
Intermediate 44 1.3- Benzodioxole-5-butanol A solution of Intermediate 43 (3.5g) in absolute ethanol (50ml) was hydrogenated at RT and atmospheric pressure over 10% palladium on carbon catalyst (200mg). Hydrogen absorption (392ml) ceased after 45min, the solution was filtered and the filtrate evaporated in vacuo to give the title alcohol as a colourless oil (3.5g).
T.l.c. (EA-CX (3:2) Rf 0.49.
The following intermediates were prepared in a similar manner to Intermediate 21.
Intermediate 45 [4-(4-Bromobutoxy)butyl]benzene (2.44g), T.l.c. [K] Rf 0.68, from 1.4- dibrcmobutane (8.6g) and benzenebutanol (2g).
Intermediate 46 [5-(4-Brcmobutoxy)pentyl1benzene (2.46g), T.l.c. [K] Rf 0.58 from 1,4-dibrcmobutane (7.89g) and benzenepentanol (2g).
Intermediate 47 [2-[(7-Bramoheptyl)oxy]ethyl1 benzene (6.2g), T.l.c. (CX-ER 40:1) Rf 0.29, from 1,7-dibromoheptane (10.5g) and benzeneethanol (5O.g).
Intermediate 48 1-[2-[(5-Branopentyl)oxy]ethyl]-4-ethylbenzene (2.19g) T.l.c. [K] Rf 0.48, frcm 1,5-dibromopentane (7.8g) and 4- ethylbenzeneethanol (1.7g).
Intermediate 49 1-[2-[(6-Branohexyl)oxy]ethyl]-4-methylbenzene (8.51g) T.l.c. [K] Rf 0.56 fran 1,6-dibranohexane (24.2g) and 4- methylbenzeethanol (4.5g).
Intermediate 50 [2-(4-Branobutaxy)ethyl]benzene (2.85g), T.l.c. [K] Rf 0.41, fran 1.4- dibranobutane (10.6g) and benzeneethanol (2g).
Intermediate 51 (2-((5-Bromopentyl)oxy]ethyl]benzene (3.8g), T.l.c. [K] Rf 0.46 from i ,5-dibranopentane (11.3g) and benzeneethanol (2g).
Intermediate 52 [3-((5-Bromopentyl)oxy]propyl]benzene (2.8g), T.l.c. [K] Rf 0.44 from 1.5- dibromopentane (10.2g) and benzenepropanol (2g).
Intermediate 53 [4-[(5-Branopentyl)oxy]butyl]benzene 4-Phenylbutanol (5.80g) was stirred in 1,5-dibromopentane (52ml) and 5N NaOH solution (50ml), and tetrabutyl anmonium bisulphate (0.87g) was added and the reaction mixture was stirred at RT fear 72h. (After 42h the NaOH layer was replaced by a fresh solution). The two layers were separated and the aqueous phase was extracted with ER (3x50ml). lhe combined organic layers were dried (Na2SO1+), and evaporated to give a clear liquid. Excess 1,5-dibromopentane was removed by distillation at 60° l.OOmmHg. The residue was chromatographed on a silica (70-230mesh, 30g) column using CX as eluant, with a slcwly increasing quantity of ER ' until the title ccmpound was obtained, which on evaporation gave a colourless oil (3.26g). T.l.c. (CX-ER (99:1)) Rf 0.15.
Intermediate 54 1-[2-[(6-Brcmohexyl)oxy]ethyl ] -4-methoxybenzene 4-Methoxybenzeneethanol (5.0g) and 1,6-dibromohexane (23.7g) were stirred rapidly at KT with tetra-n-butyl ammonium bisulphate (0.94g) and 12.5M aqueous NaOH (30ml) for 16h. The mixture was diluted with HjO (125ml), extracted with ER (3x150ml) and the combined organic extracts were washed consecutively with H2O (125ml), BR (125ml), dried and evaporated to give an oil (24.6g). The oil was purified by [FCS] eluting with ER-CX (0:100*4:96) to give the title compound as a colourless oil (8.30g). T.l.c. (CX-ER (40:1)) Rf 0.33.
Intermediate 55 7-(2-(Phenylethoxy)]-2-heptanone A solution of Intermediate 51 (2.0g) in ER (15ml) was added dropwise to magnesium (0.18g). The mixture was refluxed for lh, cooled and added during 40min to acetic anhydride (1.4g) in ER (10ml) at -78°. The suspension was stirred at -78° for 2h, warmed to -10° and treated with saturated aqueous NH^Cl (20ml). The mixture was extracted with ER (2x25ml) and the extract was washed with 5% NaOH (20ml) and BR (20ml). The dried extract was evaporated and the residue was purified on a column of silica (100ml) [L] to give the title con-pound as a colourless oil (0.70g). T.l.c. [L] Rf 0.25.
The following ketones were prepared in a similar manner: (Intermediates 57, 62 and 64 are described after Intermediate 65) Intermediate 56 7-(4-(Phenylbutoxy)]-2-heptanone (1.15g) from Intermediate 53 (3.0g) and acetic anhydride (2g). T.l.c. [L] Rf 0.25.
Intermediate 58 6-(3-Phenylpropoxy)-2-hexanone (1.3g) from Intermediate 57 (3.5g) and acetic anhydride (2.6g). T.l.c. [L] Rf 0.25.
Intermediate 59 6-(4-Phenylbutoxy)-2-hexanone (1.3g) from Intermediate 45 (3.0g) and acetic anhydride (2.3g). T.l.c. [L] Rf 0.35.
Intermediate 60 8-(2-Phenylethoxy)-3-octanone (4.35g) from Intermediate 51 (7.0g) and propionic anhydride (6.53g). T.l.c. (CX-ER 7:1) Rf 0.22.
Intermediate 61 9-(2-Phenylethoxy)-4-nonanone (2.25g) from Intermediate 51 (5.0g) and butyric anhydride (6.75g). T.l.c. [B] Rf 0.2.
Intermediate 63 7-(2-(4-Fiuorophenyl)ethoxy]-2-heptanone (1.88g) from Intermediate 62 (6.0g) and acetic anhydride (4.2g), b.p. 172°/0.7 Torr.
Intermediate 65 7-[3-(4-Methoxyphenyl)propoxy]-2-heptanone (2.17g) from Intermediate 64 (5.5g) and acetic anhydride (3.66g). T.l.c. [F] Rf 0.18.
Intermediate 57 [[3-(4-Brcmobutoxy)]propyl]benzene a mixture of 3-phenylpropanol (2g), tetrabutylammonium bisulphate (0.5g) 1,4-dibrcmobutane (9.5g) and 50% NaOH (llml) was stirred at RT for 22h, diluted with H2O (250ml) and extracted with ER (250ml). The organic phase was washed successively with H2O (250ml) and BR (250ml), dried and evaporated under reduced pressure to give a colourless oil.
Purification by [PCS] [120g], eluting with CX followed by [K] afforded the title compound as a colourless oil (2.72g).
T.l.c. (CX-EA 1:9) Rf 0.51.
Intermediate 62 1-[2-[(5-Brcmopentyl)oxy]ethyl]-4-fluorobenzene 4-Fluorobenzeneethanol (10.Og), 1,5-dibrcmopentane (29ml), tetra-nbutylammonium hydrogen sulphate (3.2g, 9mmol), and aqueous 12.5M NaOH (109ml) were stirred vigorously at KT overnight. The mixture was diluted with H2O (400ml), extracted with ER (3x200ml), and the combined organic extracts were evaporated. The residual oil was purified by [FCS] eluting with CX-ER (100:0+100:6), to give the title compound as a colourless oil (14.37g). T.l.c. (ER-CX, 19:1) Rf 0.22.
Intermediate 64 1-(3-(( 5-Bramopentyl )axy] propyl ] -4-methaxybenzene 4-Methoxybenzenepropanol (7.5g) and 1,5 dibromopentane (30.5g) were stirred rapidly at RT with tetra-n-butylammonium bisulphate (1.02g) and 12.5M aqueous NaOH (36ml) for 16h. lhe mixture was diluted with H2O (170ml), extracted with ER (3x200ml) and the combined organic extracts were washed consecutively with H2O (170ml) and BR (170ml), dried and evaporated to give an oil (34.8g). the oil was purified by [FCS] eluting with ER - CX (0:100+4:96) to give the title compound as a colourless oil (8.83g). T.l.c. (CX-ER 79:1) Rf 0.1.
Intermediate 66 1, l-Dimethyl-5- (3-phenylpropoxy )-2-pentynamine 1,1-Dimethylpropargylamine (8.5g) was added dropwise to a suspension of lithamide (from lithium (1.7g)] in liquid»ammonia (100ml) at -33°. lhe mixture was stirred for 90 min and a solution of [3-(2brcmoethoxy)propyl]benzene (21.5g) in ER (30ml) was added dropwise.
The suspension was stirred for 4h and ammonia was allowed to evaporate overnight, lhe residue was treated with H2O (100ml) and extracted with ER (3x100ml). lhe dried extract was evaporated and the residue was distilled to give the title compound as a colourless oil (3.0g) b.p. 160-165°/0.2mmHg. T.l.c. (ER) Rf 0.3.
Intermediate 67 a1- (((1 ,l-Dimethyl-5-(3-phenylpropoxy)-2,E-pentenyl]amino]methylJ-4hydroxy-1,3-benzenedimethanol A solution of methyl 5-(bromoaoetyl)-2-hydroxybenzoate (3.3g) Intermediate 66 (2.9g) and N,N-diisopropylethylamine (1.55g) in EA (50ml) was refluxed for 3h, filtered and evaporated. The residue was dissolved in ER (50ml), filtered, and added dropwise to a suspension of LiAlH^ (2g) in ER (100ml) at 0° under nitrogen. The mixture was stirred at 0° for lh at RT for lh and was treated cautiously with H2O (10ml). The mixture was acidified to pH 1 with hydrochloric acid (2M), and basified with solid KHCO3 to pH8. The ER layer was decanted off and the aqueous slurry was extracted with’CHCl3 (3x500ml). The dried extract was evaporated to leave an orange oil. The oil was purified on a column of silica (300ml) eluted with EA - methanol - triethylamine (93:7:1) to give the title conpound as a white solid (0.88g) m.p. 108109°. T.l.c. [Ml Rf 0.25.
Intermediate 68 1.1- Dimethyl-7-(2-phenylethoxy)heptanoic acid n-Butyllithium in HX (1.6M; 172ml) was added dropwise to diisopropylamine (27.5g) in 1HF (40ml) at -78° under nitrogen. Hie mixture was warmed to 0°, stirred for 45min, and isobutyric acid (12.Og) was added dropwise. The resulting suspension was stirred at RT for 4h and Intermediate 51 (25.0g) was added dropwise. The mixture was stirred for 16h at KT, treated slowly with hydrochloric acid (2M; 350ml), and extracted with ER (2x250ml). The dried extract was evaporated and the residue was purified on a column of silica (Merck. 9385; 300ml) [B] to give the title compound as a colourless oil (17.Og). T.l.c. [L] Rf 0.35.
Intermediate 69 l-l-Dimethyl-6-(2-phenylethoxy)hexylcarbamic acid, phenylmethyl ester Ethyl chloroformate (3.26g) in acetone (10ml) was added to a solution of Intermediate 68 (8.0g) and triethylamine (3.03g) in acetone (100ml) and H2O (10ml) at 0°. The mixture was stirred for 40min at 0° and sodium azide (2.25g) in H2O (25ml) was added dropwise. The resulting suspension was stirred at RT for 30min, diluted with H2O (200ml), and extracted with toluene (2x200ml). The dried (Na2SO4) extract was evaporated to half-volume, heated at 70-80° for 2h, and toluene was removed under reduced pressure. The resulting isocyanate in benzyl alcohol (20ml) was heated at 80-83° for 60h and benzyl alcohol was removed under reduced pressure (1 Torr). The residue was purified in a column of silica (Merck 9385; 300ml) eluted with CX - ER (17:3) to give the title compound as a colourless oil (7.45g). T.l.c.
[L] Rf 0.25.
Intermediate 70 1.1- Dimethyl-6-(2-phenylethoxy)hexanamine A solution of Intermediate 69 (6.8g) in ethanol (100ml) was hydrogenated over 10% palladium on charcoal (0.5g) for 40min filtered, and evaporated to give the title compound as a colourless oil (4.3g). 4G Intermediate 71 Methyl 5-[2-(dimethylanino)-l-hydroxyethyl1-2-(pheny lmethoxy)benzoate Dimethylamine (33% in ethanol, 156ml) was added to a stirred suspension of methyl 5-(bromoacetyl )-2-(pheny lmethoxy) benzoate (105.8g) in absolute ethanol (ll) and THF (ll). The resulting solution was stirred at KT for 2h, treated with NaBHu (25g) and stirred at KT overnight.
The solvent was removed in vacuo and H20 (500ml) was added to the residue. The mixture was extracted with EA (2x500ml), the combined extracts were washed with HjO and BR, dried (Na2SO^) and concentrated in vacuo. The product was purified twice by [PCS] eluted with EA-methanol-triethylamine (80:20:1) to give the title compound as a fawn solid (59.8g) m.p. 79-81°.
Intermediate 72 (R)-Methyl 5-[2-(dimethylamino)-l-hydroxyethyl]-2-(phenylmethoxy)benzoate[S- (R*,R*)-2,3-bis[(4-methylbenzoyl)oxyIbutanedioate (1:1) (salt).
Intermediate 71 (50g) in hot methanol (250ml) was mixed with (-)-di-p-toluoyl tartaric acid, monohydrate (60g) in hot methanol (250ml). The resulting precipitate was collected by filtration and recrystallised three times frcm methanol (25ml/gram) to give the title 18 2θ compound as white needles (16.4g). m.p. 169-170° [α]θ * - 103.3°(c 0.51 in CH3OH) Intermediate 73 (R)-Methyl 5-[2-(dimethylamino)-l-hydroxyethyl]-2-(phenylmethoxy)benzoate Intermediate 72 (16.4g) was partitioned between EA (175ml) and 6N ammonium hydroxide (8.4ml) in H2O (175ml). Ihe organic layer was washed with 8% NaHCO3 (2x100ml), BR, dried (Na2SOu) and concentrated in vacuo to give the title compound as a viscous oil (7.9g) T.l.c. (EA-methanol-triethylamine 80:20:1) Rf = 0.23.
Intermediate 74 (R) - β-Hydroxy- 3- (methoxycarbony 1) -N, N, N-1 r imethy 1 -4-( phenylmethoxy) benzeneethananinium iodide Intermediate 73 (7.85g) and methyl iodide (17.5ml) in acetone (55ml) was stirred at reflux under nitrogen for 3h. lhe acetone was removed in vacuo and CHC13 (100ml) was added to the residue. The resulting precipitate was collected by filtration and dried in vacuo (12.2g). Recrystallisation from methanol gave the title compound as an off-white solid (4.5g) m.p. 85-120o [α]θ -32.2° (c 0.7 in DMSO) Intermediate 75 (R )-Methyl 5-ox iranyl-2-(phenylmethaxy)benzoate A warm suspension of Intermediate 74 in dry acetonitrile (200ml) was treated with tetramethylammonium fluoride-bi-methanol solvate (5.5g) and stirred at reflux, with continuous removal of the distillate, for 2.5h. The cooled reaction mixture was filtered and the filtrate was concentrated in vacuo to a semi-solid. Dry ER (100ml) was added and the mixture was refiltered. The filtrate was concentrated to an oil which was purified by [FCS] eluting with CX-EA-triethylamine 80:20:1 to 23.3° give the title compound as a colourless oil (1.98g). [ο]θ + 19.9° (c 0.86 in benzene) T.l.c. (CX-EA-triethylamine 80:20:1) Rf = 0.14.
Intermediate 76 (R)-Methyl 5-[l-hydroxy-2-[(phenylmethyl)[6-(3-phenylpropoxy)hexyl]amino]ethyl]- 2-(pheny lmethoxy)benzoate Intermediate 75 (1.9g) and Intermediate 22, free base (2.17g) in methanol (50ml) were stirred at reflux, under nitrogen, for 6h. The solvent was removed in vacuo and the residual oil was purified by [PCS] eluting with CX-EA-triethylamine 75:25:1 to give the title conpound as a pale yellow oil (2.1g). [α]θ -62.4° (c 0.74 in T.l.c.
(CX-EA-triethylamine 80:20:1) Rf = 0.12.
Intermediate 77 (R)-(-)-4-(Phenylmethoxy)-q1~[[(phenylmethyl)[6-(3-phenylpropoxy)hexyl]amino]methyl]-1,3-benzenedimethanol Intermediate 76 (2.0g) in dry THF (40ml) was added to a stirred suspension of LiAlH^ (300mg) in dry THF (40ml) at RT, under nitrogen. The reaction mixture was placed in an oil-bath, preheated to 80°, arid stirred at reflux for 5 min. The cooled mixture was treated cautiously with HgO (40ml) and ER (40ml). The phases were separated and the aqueous phase was re-extracted with ER (50ml).
The combined organic phases were washed with HgO and BR, dried (Na2SO4) and concentrated in vacuo. [FCS] using CX-EA-triethylamine 66:33:1 as eluant gave the titlepCompound as a clear, colourless oil (1.70g). [a]21 - 64.6° (c 0.6 in CHClg) T.l.c. (CX-EA-triethylamine 66:33:1) Rf = 0.15 In the following examples the products of examples ,7,11,12.24 and 26 are intermediates in which either 3 the nitrogen atom (NR in formula IX above) and/or the saligenium ring (see formula X above) is protected. Subsequent removal of the protecting groups to give compounds of formula (I) is described in examples 13,14,25. Example 1 . 4-Hydroxy-a -[[[6-(2-phenylethoxy)hexyl]amino]methyl] -1,3-benzenedimethanol. hydrate A mixture of Intermediate 1 (0.93g), Intermediate 2 (1.6g), pyridine (1ml) and DMF (25ml) was left at RT for 2 weeks. The resulting solution was evaporated and the residue was purified on a column of silica (Merck 9385: 250ml) [I] to give a yellow oil. The oil was triturated with ER to give the title compound as a cream solid (0.20g) m.p. 89-91°.
T.l.c. [M] Rf 0.1.
Example 2 4-Hydroxy-a1-.[ [ [6-(4-phenylbutoxy )hexyl ]amino]methyl ]-l, 3-benz.en€dimethanol A solution of Intermediate 1 (8.9g), potassium iodide (4.0g), triethylamine (5ml) and DMF (250ml) at 70° was treated dropwise with Intermediate 3 (7.5g). The solution was heated at 65-70° for lh and DMF was removed under reduced pressure. The residue was treated with HgO (200ml) and the resulting emulsion was extracted with EA (3x300ml). The combined extracts were washed with HgO (2x50ml) and BR (50ml), dried and evaporated Trituration of the residue with ER/10% EA (200ml) for 16h gave a suspension fran which the title compound was collected as a white solid (2.6g), m.p. 75.5-76.5°. T.l.c. [M] Rf 0.2.
Example 3 4-Hydroxy-a!-[[[6-(4-phenylbutoxy)hexyl]amino]methyl]—1,3— benzened imethanol A solution of Intermediate 4 (2.2g) and Intermediate 6 (l.Og) in absolute ethanol (25ml) was hydrogenated at KT and atmospheric pressure over 10% palladium on carbon catalyst (0.2g). The mixture was filtered through Hyflo and evaporated to give an oil. Purification by [FCTS] (40g) [N] gave an oil which on trituration with ER afforded the title compound as a white solid (0.77g) m.p. 75-76°, mixed m.p. 74-76° with the product of Example 2. T.l.c. ΕΝ [N] Rf 0.31.
Example 4 4-Hydroxy^g1-[[[6-(4-phenylbutoxy)hexyl)]amino]methyl]-l,3benzened imethanol Intermediate 6 (0.5g)) was added to a stirred suspension of Intermediate *5 l (0.5g) in methanol (5ml) at 23°. The mixture was stirred for 0.5h, NaBH^ (0.5g) was added and stirring continued for 7h. The mixture was diluted with H20 (50ml), extracted with EA (2x25ml) and the organic phase was washed with BR (25ml), dried and evaporated to give an oil. Purification by [FCTS] (30g) afforded an oil which on trituration with cold ER gave the title compound as a white solid (0.25g), m.p. 76-77°, mixed m.p. 75-76° with the product of Example 2.
T.l.c. EN[N] Rf 0.31.
Example 5 4-Hydroxy-g1-[[[6-(4-phenylbutoxy)hexyl](pheny lmethyl)amino]methyl]25 1,3-benzenedimethanol A solution of Intermediate 7 (51g) and 4-bromoaoetyl-2(hydroxymethyl)phenol diacetate [prepared from 36.25g of 4-acetyl-2(hydroxymethyl)phenol diacetate] in CHC13 (410ml) was stirred at the reflux for 24h, cooled and concentrated under reduced pressure. The residual oil was dissolved in toluene (75ml) and concentrated. The oil was dissolved in toluene (125ml), washed with H2O (150ml) and BR (50ml). The agueous solutions were extracted with toluene (30ml) and the combined extracts were washed with H2O (50ml) and concentrated. The crude ketoamine diacetate was stirred in ethanol (155ml) and 10N hydrochloric acid (48ml) in H2O (58ml) was added dropwise with stirring, the temperature being maintained below 20°. After being SI allowed to stand at 0° for 2 days the solution was treated with ethanol (180ml) and NaOH (17.6g) in H2O (18ml) whilst keeping the temperature below 15°. NaBH^ (11.06g) and NaOH (2.11g) in H2O were added, followed after 24h by more NaBH^ (9.5g) over a period of 48h. The mixture was neutralised with 2N sulphuric acid and concentrated to a slurry which was partitioned between 2N Na2GO3 (100ml) and EA (200ml). The organic layer was treated with a further quantity of 2N Na2CD3 (lOOtnl) and EA (200ml). The combined organic extracts were washed, dried and evaporat ed. The crude tribl was chromatographed on Sorbsil (Registered Trade Mark) (700g), [G] to give the title oorpound (26.5g) identified by its n.m.r. spectrum.
Example 6 4-Hydroxy-g1-[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3benzened imethanol A solution of Intermediate 8 (0.4g) in absolute ethanol (25ml) was I hydrogenated at 23° and atmospheric pressure over 10% palladium on carbon (0.2g) and 10% platinum on carbon (0.2g) catalysts. The mixture was filtered through Hyflo and evaporated to give an oil. Purification by [FCTS] (20g) [N] afforded an oil which on trituration with ER gave the title ccmpound as a white solid (0.21g) m.p. 76.5 - 77.5°, mixed m.p. 75.5 - 76.5° with the product of Example 2.
T.l.c. HM [N] Rf 0.31.
Example 7 2,2-Dimethyl-q- [ [ [6-(4-phenylbutoxy) hexyl] anino]methyl]-4H-l,3benzodioxin-6-methan0l A solution of Intermediate 10 (lg) in absolute ethanol (20ml) was hydrogenated at 23° and atmospheric pressure over 10% palladium on carbon (O.lg) and 10% platinum on carbon (O.lg) catalysts. The mixture was filtered through Hyflo and evaporated in vacuo to give an oil which slowly crystallised. The solid was slurried in HX, filtered off and dried to give the title compound as white crystals (0.72g) m.p. 68-70°, T.l.c. HM (EA - MeOH 19:1) Rf 0.45.
Example 8 4-Hydroxy-g1-[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-l,3benzened imethanol A solution of Intermediate 12 (0.3g) in dry THF (5ml) was added to a stirred suspension of LiAlH^ (0.26g) in dry THF (15ml) at 0° under nitrogen. The mixture was stirred at 23° for 20h, diluted cautiously with H2O (30ml), acidified to pH5 with 2M hydrochloric acid, basified to pH8 with NaHCO3 and extracted with EA (3x50ml). The organic phase was washed with BR (50ml), dried (NajSO^) and evaporated to give an oil which was purified by [FCTS] [N] to give an oil. Trituration with cold ER afforded the title ccmpound as a white solid (0.064g) m.p. 75-76.5° . mixed m.p. 75-76° with the product of Example 2. T.l.c. EN[N] Rf 0.31.
Example 9 4-Hydroxy-g1- [ [ [6-(4-phenylbutoxy )hexyl ] aminojmethyl 1-1,3benzenedimethanol A solution of Intermediate 13 (0.91g) in THF (10ml) was added over 15 min to a stirred solution of methyl 5-(bromoacetyl)-2-hydroxybenzoate (lg) and N,N-diisopropylethylamine (0.85g) in 1HF (10ml) at 0°. The mixture was stirred at 0° for 2h, diluted with ether (50ml), washed with 0.5M hydrochloric acid (50ml), 8% NaHC03 (50ml), BR (50ml), dried and evaporated to give an oil. Purification by [FCS] (60g) [O] afforded the intermediate glycyl compound as an oil (0.6g). A solution of this oil (0.6g) in dry THF (5ml) was added to a stirred slurry of LiAlH^ (0.25g) in dry THF (25ml) under nitrogen at 23°. The mixture was stirred for 18h, diluted cautiously with H2O (50ml), acidified to pH5 with 2M hydrochloric acid, basified to pH8 with NaHCO3 and extracted with EA (2x100ml). The dried extract was evaporated to give an oil which was purified by [FCTS] (20g) [N] to give an oil which on trituration with ER afforded the title ccmpound as a white powder (0.12g) m.p 75.5-76.5°, mixed m.p. 75-76° with the product of Example 2. T.l.c. ΕΝ [N] Rf 0.31.
Example 10 4-Hydroxy-ql-[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3benzenedimethanol.
A solution of Intermediate 14 (0.58g) in dry 1HF (10ml) was added over lOmin to a stirred suspension of LiAlHu (0.5g) in dry THF (25ml) at 0° under nitrogen. The mixture was stirred at 23° for 18h, diluted cautiously with H2O (50ml), acidified to pH5 with 2M hydrochloric acid, basified to pH8 with NaHOO3 and extracted with EA (3x50ml). The extract was washed with BR (50ml) dried (Na2SO,J and evaporated to give an oil which was purified by [FCTS][N] to give a pale yellow oil. Trituration with cold ER gave the title conpound as a white solid (0.115g) m.p. 76-77° mixed m.p. 75.5-76.5 with the product of Example 2. T.l.c.
EN[N] Rf 0.31.
Example 11 2,2-Dimethyl-a- [ 116-(4-phenylbutoxy)hexyl] (phenyImethyl )anino]methyl]4H-1,3-benzodioxin-6-methanol A solution of Intermediate 16 (0.24g) and Intermediate 7 (0.8g) in dry THF (3ml) was refluxed under nitrogen for 24h. The mixture was evaporated and the residue purified by [PCS] [J] to afford the title conpound as a pale yellow oil (0.18g). T.l.c. [O] Rf 0.49.
Example 12 2,2-Dimethyl-g- [ [ [6-(4-phenylbutoxy)hexyl] (phenylmethyl)amino]methyl]4H-1,3-benzodioxin-6-methanol A solution of Intermediate 15 (0.2g) and Intermediate 7 (0.7g) in dry THF (5ml) was refluxed under nitrogen for 18h. The mixture was diluted with ER (15ml), washed with 8% NaHCO3 solution (15ml), BR (10ml), dried and evaporated to give an oil (0.8g). Purification by [FCS] (20g) [J] afforded the title compound as a pale yellow oil (0.09g). T.l.c.
[O] Rf 0.49.
Example 13 4-Hydroxy-q1-[[[6-(4-phenylbutoxy)hexyl] anino]methyl]-1,325 benzened imethanol A solution of the product of Example 7 (0.3g) in methanol (2ml) was diluted with 2M hydrochloric acid (2ml) and the solution was kept at 23° for 5h. EA (15ml) was added and the mixture washed with 8% NaHC03 (15ml), BR (15ml), dried and evaporated in vacuo to give a colourless oil. Trituration with ER afforded the title compound as a white solid (0.23g) m.p. 76-77°, mixed m.p. 75.5 -77° with the product of Example 2. T.l.c. EN[N] Rf 0.31.
Example 14 4-Hydroxy-g1-[[[6-(4-phenylbutoxy) he?yl larnino] methyl]-1,3benzened imethanol lhe product described in Example 5 (230g) in ethanol (1.3A) was reduced ty hydrogen in the presence of 10% palladium-on-carbon catalyst (46.5% paste in H2O; 60g). Catalyst and solvent were removed and ER (2a) was added to the residue. The solution was decanted from a little insoluble gum and left to stand overnight. Filtration of the mixture afforded the title compound (147g), m.p. 75-77°.
Example 15 4-Hydroxy-g1- [ [ [6-( 2-phenylbutoxy) hexyl] amino]methyl ]-l ,3benzened imethanol, hydrate A solution of Intermediate 20 (30mg) in EA (2ftnl) was hydrogenated over palladium-charcoal (10%, ~20mg) for 5h, filtered through Hyflo and concentrated under reduced pressure to give the title compound as a pale yellcw solid (27mg). T.l.c. (EA-ethanol-NH3 10:1:1) Rf 0.3.
H.p.l.c. Column:5u Hypersil 5nrnxl0mm; λ max : 276nm; Flowrate : 2ml/min; Eluant : HX-EA-Isopropanol-NH3 10:1:1:0.15 Retention time 11.5min.
Example 16 4-Hydroxy-g1-[[[6-(4-phenylbutoxy)hexyl] amino]methyl]-l,3benzenedimethanol benzoate salt A solution of the compound of Example 2 (2.3g) in EA (5ml) at 40° was added to a solution of benzoic acid (0.7g) in EA (5ml) at 40°. lhe solution was cooled to 0° and EA was decanted from the resulting solid. The solid was washed with ER (3x5ml) and recrystallised from EA to give the title canpound as a white solid m.p. 117-117.5°.
Example 17 4-Hydroxy-g[[[6-(4-phenylbutoxy)hexyl] amino]methyl1-1,3benzenedimethanol 2-hydroxybenzoate (salt).
A solution of 2-hydroxybenzoic acid (0.83g) in warm isopropanol (10ml) was added to the ccnpound of Example 2 (2.50g) in isopropanol (10ml). The mixture was aged overnight at anbient temperature then the product was collected, washed with isopropanol (3x5ml) and dried in vacuo at 60°, to give the title salt as a colourless solid, m.p. 134-135° The following salts (Examples 18-21) were prepared in a similar manner fran the compound of Example 2. •4 5 Example 18 4-Hydroxy-a1-[[[6-(4-phenylbutaxy)hexyl]anino]methyl]-l,3- benzenedimethanol 4-chlorobenzoate (salt) The product melted at 117-119°, partially resolidified and remelted at 134°. 10 Example 19 4-hydroxy-a1-[ [ [6-(4-phenylbutoxy)hexyl]amino]methyl]-l,3- benzenedimethanol 4-hydroxybenzoate (salt), m.p. 136.5-138°. Example 20 4-Hydroxy-a1-[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-l,3benzenedimethanol 1-hydroxy-2-naphthalenecarboxylate (salt), m.p. 137-138° 15 Example 21 4-Hydroxy-a1-[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-l,3benzenedimethanol 3-hydroxy-2-naphthalenecarboxylate (salt), m.p. 135-137° 20 Example 22 4-Hydroxy-a1-[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-l,3- benzenedimethanol sulphate (2:1) (salt) Sulphuric acid (98% w/w, 61$ng) was added to ethanol (10ml) and a portion of the solution (5.2ml) was added to a warm solution of the base 2E of the compound of Example 2 (2.5g) in ethanol (10ml). On being allowed to stand in an open necked flask for 24h the solution deposited white needles which were filtered off, washed with ethanol (2x5ml) and dried at 50° in vacuo to qive the title salt (1.89g), m.p. 117.5-119.5°. 30 Example 23 4-Hydroxy-a1-[[[6-(3-phenylpropoxy)hexyl] amino] methyl]-l,3- benzened imethanol A mixture of Intermediate 1 (0.84g), Intermediate 21 (l.Og), Ν,Νdiisopropylethylamine (0.706g, 0.95ml) and DMF (7.3ml) was heated at 80° ίί 6' for lh. The clear brown solution was diluted with H2O (75ml), acidified to pH4 with 2N hydrochloric acid and then basified to pH8 with solid KHCO3. The cloudy aqueous phase was extracted with EA (2x75ml) and the combined extracts were washed successively with H2O (75ml) and BR (35ml). The oombined dried (Na29O^) extracts were evaporated and the residual oil was purified by [FCS][I] to give, after trituration with ER (25ml) the title compound (0.279g) as a white solid m.p. 77-78°.
T.l.c. [I] Rf 0.13.
Example 24 4-Hydroxy-g1-[[(phenylmethyl)-[6-(3-phenylpropoxy)hexyl] an ino] methyl]1,3-benzened imethanol Intermediate 23 was added during 15min to a solution of sodium bis(2methoxyethoxyjaluminium hydride (3.4M solution in toluene; 33ml) and CH2C12 (50ml), whilst maintaining the temperature between 4° and 18°, under nitrogen. After 1.75h at 15° the mixture was cooled to 5° and treated very cautiously with H2O (10ml). The filtrate was evaporated under reduced pressure and the residue in EA (250ml) was treated with 2N hydrochloric acid (250ml). The organic layer was washed successively with 2N Na2GO3 solution (200ml) and H2O (200ml), dried and evaporated to give the title ccmpound as an orange oil (15.8g). T.l.c. (ER) Rf 0.3.
Example 25 4-Hydroxy-g1-[ [ [6-(3-phenylpropaxy)hexyl]anino]methyl]-l,3benzened imethanol The product of Example 24 (19g) in ethanol (150ml) was hydrogenated in the presence of 10% palladium-on-charcoal catalyst (5.2g). After 2h 40min the mixture was filtered and the filtrate evaporated under reduced pressure to a pale yellow oil, which crystallised from EA to give the title conpound as a white solid, (10.lg) m.p. 82-84°.
Analysis Found: C,71.76;H,8.60;N,3.43.
C25H35NOU reQuires C,71.78;H,8.79;N,3.49%.
Exanple 26 4-Hydroxy-g1- [ [(phenylmethyl)- [6-( 3-phenylpropoxy) hexyl ] am ino] methyl ] 1,3-benzened imethanol A solution of 4-bromoacety1-2-(hydroxymethyl)phenol diacetate [prepared frcm 4-acetyl-2-(hydroxymethyl)phenol diacetate (30g)] in CHC13 (221ml) was treated with propylene oxide (16.7g) and Intermediate 22 hydrochloride (43.4g). The mixture was stirred and heated at reflux for 24h, and allowed to cool to RT. Solvent was removed under reduced pressure, the residue was dissolved in toluene (200ml) and washed with H2O (2x50ml). The toluene solution was evaporated to dryness and the residue was dissolved in a mixture of ethanol (270ml), H2O (117ml), and ION hydrochloric acid (89ml). The mixture was allowed to stand at RT for 48h and evaporated to dryness to give an oil. This crude hydrochloride was dissolved in ethanol (283ml) and the stirred solution was treated with a solution of NaOH (3.53g) in H20 (3.53ml) keeping the temperature below 20°. The solution was cooled to below 10°, and a solution of NaBH^ (9.15g) and NaOH (1.26g) in H2O (34.9ml) was added over 0.5h keeping the temperature below 10°. The mixture was stirred at 20° for 24h and then adjusted to pH 7.3 with 5N sulphuric acid and evaporated to dryness. The residue was dissolved in a mixture of EA (291ml) and 2N Na2OO3 (176ml). The aqueous phase was extracted with EA (2x117ml), the combined EA solution was washed with IN Na2OO3 (162ml) and H2O (8x162ml) and then evaporated to dryness. The resulting oil was purified by column chromatography (Sorbsil, 500g) [O] to give the title 2o compound as an oil (17.0g). This compound was reduced, as described in Example 25, to the compound of Example 23.
Example 27 4-Hydroxy-q1-[[[6-(3-phenylpropoxy)hexyl] amino Imethyl]-1,3benzenedimethanol, sulphate (2:1) salt A solution of concentrated sulphuric acid (0.3g) in ethanol (5ml) was added to a warm solution of the base of Example 23 (2.4g) in ethanol (10ml). The title salt precipitated as a white solid (1.9g), m.p. 111-112°.
Exanple 28 4-Hydroxy-q1-[[[6-[4-(2-methoxyphenyl)butoxy]hexyl]amino]methyl]-l,3benzened imethanol Intermediate 24 (2.0g) was added dropwise to a solution of Intermediate 1 (2.13g), triethylamine (5ml), and potassium iodide (0.95g) in DMF (50ml) at 70°. The solution was heated at 70-75° for lh and added to H2O (800ml). The resulting emulsion was extracted with EA (3x200ml) and the dried extract was evaporated to leave an orange oil. The oil was purified on a column of silica (150ml) [I] to leave a colourless oil.
The oil was crystallised from EA to give the title compound as an off-white solid (0.80g) m.p. 52-54°. T.l.c. [Ml Rf 0.2.
Example 29 4-Hydroxy-g1- [ [ [4- [(6-phenylhexyl )oxy] butyl] aminolmethyl ]-l ,3benzened imethanol Intermediate 29 (l.Og) was added dropwise to a solution of Intermediate 1 (1.2g) and triethylamine (2ml) in DMF (30ml) at 60°. The solution was stirred at 60-70° for 4h and added to H2O (500hil). The resulting emulsion was extracted with EA (3x150ml) and the dried extract was evaporated to leave a brown oil. The oil was purified on a column of silica (Merck 9385; 150ml) [I] to leave a yellow gum. The gum was repurified on a column of silica (Merck 9385, 50ml) eluted with EA-methanol (93:7) to leave a colourless oil. Trituration of the oil with ER (10ml) gave the title compound as a white solid (0.07g) m.p. 75-77°. T.l.c. [M] Rf 0.15 Exanple 30 a1- [ [ [6- [2-(2,6-Dimethylphenyl )ethoxy]hexyl]amino]methyl 1-4-hydroxy1,3-benzened imethanol, hemihydrate Intermediate 30 (2.0g) was added drcpwise to a solution of Intermediate 1 (2.34g), potassium iodide (0.9g) and triethylamine (4g) in DMF (60ml) at 60°. The solution was stirred at 60-70° for lh and added to H2O (800ml). The emulsion was evaporated to leave a yellow oil.
Purification of the oil on a column of silica (100ml) [I] gave a colourless oil. Trituration of this oil with ER (25ml) gave a white solid which was crystallised from EA to give the title conpound as a white solid (0.43g) m.p. 83-86°. T.l.c. [M] Rf 0.15 The following Examples were prepared in a similar manner to that described for Example 23 frem Intermediate 1 and the other Intermediate shown in the Table.
Example 31 4-Hydroxy-a1-(((6-(4-(4-methoxyphenyl)butoxy]hexyl]aminolmethyl]-1,3-benzenedimethanol Example 32 4-Hydroxy-a1-([[5-[(5-phenylpentyl)oxy]pentyl]amino]methyl] 1,3-benzened imethanol Example 33 a1_[([6-[2-(4-Chlorophenyl)ethoxy]hexyl]amino]methyl]-4hydroxy-1,3-benzenedimethanol Example 34 a1-! [ [6-[3-(4-Flu<>rophenyl)propoxyJhexyl]arni.nolmethyl]-4- Example 35 hydroxy-1,3-benzened imethanol 4-Hydroxy-a1-[[8-((2-phenylethoxy)octyl] amino]methyl]-1,3benzenedimethanol Example 36 4-Hydroxy-a1-[I[6-[(5-phenylpentyl)oxy]hexyl]amino]methyl]1,3-benzenedimethanol Example 37 a1-[[[6-[2-(4-Ethylphenyl)ethoxy]hexyl]amino]methyl]-4hydroxy-1,3-benzenedimethanol Example 38 4-Hydroxy-a1-[[[7-(3-phenylpropoxy)heptyllarnino]methyl]1,3-benzenedimethanol Example 39 a1_[[[6-[4-(1,3-Benzodioxol-5-yl)butoxy]hexyl]amino] methyl4-hydroxy-l,3-benzenedimethanol Example 40 a1-[[[6-[2-(3-Chloropheny1)ethoxy]hexyl]ami no]methyl]-4hydroxy-1,3-benzened imethanol Example 41 4-Hydroxy-a1-[[[6-(phenylmethoxy)hexyl] aminojmethyl]-1,3- benzened imethanol Example 42 a1-![[6-[3-(2-Fluorophenyl)propoxy]hexyl]amino]methyl]-4hydroxy-1,3-benzenedimethanol Example 43 4-Hydroxy-a1-![[(4-phenylbutoxy)butyl]amino]methyl]-l,3- benzened imethanol Example 44 4-Hydroxy-a1-[ [ [ [ 4-(5-phenylpentyl, oxy] butyl larnino] methyl] 1,3-benzenedimethanol Example 45 4-Hydroxy-a1-[[7-[(2-phenylethoxy)heptyl] aminojmethyl]-1,3 benzenedimethanol Example 46 a1-[[[5-[2-(4-Ethylphenyl)ethoxy]pentyl]amino]methyl]-4hydroxy-1,3-benzened imethanol Example 47 4-Hydroxy-a^([[6-[2-(4-methylphenyl)ethoxy]hexyl]amino]methyl]-1,3-benzenedimethanol Example 48 4-Hydroxy-a1-[[[4-(2-phenylethoxy)butyl]amino]methyl]-l,3- benzenedimethanol Example 49 4-Hydroxy-a1-[[[5-(2-phenylethoxy)pentyl]amino]methyl]-1,3 Example 50 benzenedimethanol hydrochloride 4-Hydroxy-a1-[[[5-(3-phenylpropoxy)pentyllarnino]methyl]1,3-benzenedimethanol hydrochloride 6» Example Intermediate Chromatography eluents EA-Methanol-NEt3 M.p. °C 31 31 90:10:1* 81-82 32 32 85:15:1* 66-67 33 33 89:10:1 89-91 34 34 89:10:1 63-67 35 35 No chromatography 97-99 36 36 + KI 89:10:1 75-77 37 37 + KI 89:10:1 96-99 38 38 89:10:1 72-75 39 39 4:1:0* 68-70 40 40 89:10:1 76-78 41 + . 79:20:1 69-70 42 41 89:10:1 79-81 43 45 3:1:0* 63-68 44 46 7:10:1 66-71 45 47 90:10:1 80-81 46 48 3:1:0* 75-78 47 49 3:1:0* 88.5-93.5 48 50 4:1:0* 75-78 49 51 3:1* 66-67 (hydrochloride) 50 52 3:1* 50-56 (Hydrochloride) * lhe silica was deactivated with NEt3 + [l-[(6-Bromohexyl)oxy]methyl]benzene r Example 51 4-Hydroxy-q1-[ [ [5-(4-phenylbutoxy)pentyl)aminolmethyl]-l,3benzened imethanol A mixture of Intermediate 1 (1.15g), DMF (10ml), N,N5 diisopropylethylamine (1.2g) and Intermediate 53 (0.9g) was heated at 75° for 2h. The mixture was diluted with H20 (150tnl) acidified to pH4 with 2M hydrochloric acid, basified to pH8 with solid KHCO3 and extracted with EA (2x80ml). The extracts were washed with H20 (50ml), BR (50ml), dried (NajSO^) and evaporated in vacuo to give an oil which was purified by [FCTS] using EA - methanol - triethylamine (85:15:1) as the eluant to give the product as an oil. This was dissolved in warm EA (15ml) and cooled to give the title compound as an off-white solid (0.35g) m.p. 117-119°, T.l.c. EN (EA - CH3OH 17:3) Rf 0.32.
Exanple 52 4-Hydroxy-a1- [ [ [6- [2-(4-methoxyphenyl )ethaxy]hexyl]aminolmethyl]-1,3benzened imethanol A mixture of Intermediate 1 (0.95g), Intermediate 54 (1.50g) and N,N diisopropylethylamine (1.35ml) in DMF (molecular sieve dried, 11ml) was heated at 80° for lh under nitrogen. Ihe clear brown solution was basified with 8% NaH003 solution (36ml) and the cloudy mixture was extracted with EA (3x110ml). The combined organic extracts were washed consecutively with H2O (110ml) and BR (50ml), dried (Na2SOu) and evaporated. Ihe resultant oil (2.43g) was purified by [FCS][I] to give a solid which, on trituration with ER (25ml) gave the title compound as a white solid (0.582g), m.p. 101-102°.
Analysis Found: C,68.65;H,8.55;N,3.35.
C2*»H35NO5 re<3uires C,69.05;H,8.45;N,3.35%.
Example 53 4-Hydroxy-a1-[[[l-methyl-6-(2-phenylethoxy)hexyl]amino]methyl]-l,3benzened imethanol A solution of Intermediate 4 (0.94g) and Intermediate 55 (0.6g) in ethanol (40ml) was hydrogenated over 10% palladium on charcoal (0.25g) and 5% platinum on charcoal (0.25g) for 20h, filtered, and evaporated.
The residue was.purified on a column of silica (Merck 9385, 50ml) [I] 2 to give a colourless oil. Trituration of the oil with ER (10ml) gave the title compound as a white solid (0.3g), m.p. 68-76°.
T.l.c. [M] Rf 0.2.
Exanple 54 4-Hydroxy-g1-[[[l-methyl-6-(4-phenylbutoxy)hexyl] amino] methyl]-!,3benzened imethanol A solution of Intermediate 4 (1.39g) and Intermediate 56 (l.Og) in ethanol (40ml) was hydrogenated over 10% palladium on charcoal (0.2g) and 5% platinum on charcoal (0.2g) for 26h, filtered and evaporated, lhe residue was purified on a column of silica (Merck 9385; 100ml) [I] to give the title ccmpound as a white solid (0.62g) m.p. 57-60°.
T.l.c. [M] Rf 0.2.
Exanple 55 4-Hydroxy-g[[[1-methyl-5-(3-phenylpropoxy)pentyl] amino]methyl]—1,3— benzened imethanol A solution of Intermediate 4 (1.6g) and Intermediate 58 (l.Og) in ethanol (60ml) was hydrogenated over 10% palladium on charcoal (0.3g) and 5% platinum on charcoal (0.3g) for 20h, filtered and evaporated.
The residue was purified on a column of silica (Merck 9385; 90ml) [I] to give a colourless oil. Trituration of the oil with ER (20ml) gave the title ccmpound as a white solid (0.8g) m.p. 86-93°.
T.l.c. [M] Rf 0.25.
Exanple 56 4-Hydroxy-g1-[[[l-ethyl-6-(2-phenylethoxy)hexyl)amino]methyl]-1,3benzened imethanol.
A solution of Intermediate 60 (l.Og) and Intermediate 4 (2.19) in absolute ethanol (60ml) was hydrogenated over a mixture of palladium on carbon catalyst (200mg) and platinum on carbon catalyst (200mg) at RT and atmospheric pressure. After 18h, the mixture was filtered and the filtrate evaporated in vacuo to give a yellow solid. Purification by [FCTS] (120g) with EA - methanol - triethylamine (95:5:1) as eluant gave the title ccnpound as a white solid (480mg) m.p. 82-84°.
T.l.c. EN (EA-methanol)(19:l) Rf 0.37.
Example 57 4-Hydroxy-g1-[[[l-methyl-5-(4-phenylbutoxy)pentyl]amino]methyl]-1,3benzened imethanol A solution of Intermediate 4 (l»45g) and Intermediate 59 (l.Og) in ethanol (60ml) was hydrogenated over 10% palladium on charcoal (0.3g) and 5% platinum on charcoal (0.3g) for 20h, filtered and evaporated. The residue was purified on a column of silica (Merck 9385; 100ml) [I] to give a colourless oil. Trituration of the oil with ER (20ml) gave the title compound as a white solid (0.9g) m.p. 64-66°.
T.l.c. [M] Rf 0.2.
Example 58 4-Hydroxy-g1- [ [ [5-(2-phenylethoxy)-l-propylpentyl]anino]methyl]-l,3benzened imethanol benzoate salt.
A solution of Intermediate 4 (2.77g) and Intermediate 61 (2.0g) in ethanol (120ml) was hydrogenated over 10% palladium on charcoal (0.25g) and 5% platinum on charcoal (0.45g) for 22h, filtered and evaporated. The residue was purified on a column of silica (Merck 9385; 150ml) eluted with EA - methanol - triethylamine (19:1:0.1) to give a colourless oil (0.5g). The oil in CHC13 (5ml) was added to benzoic acid (0.2g) in CHC13 (5ml) and the CHC13 was evaporated. The residue was triturated with ER (3x25ml) to give the title compound as a white solid (0.36g) m.p. 67-69°. T.l.c. [M] Rf 0.35.
Exanple 59 g1— [ [ [6-[2-(4-Fluorophenyl)ethoxy]-l-methylhexyl]amino]methyl]-4hydroxy-1,3-benzened imethanol Intermediate 63 (623mg) and Intermediate 4 (896mg) in ethanol (20ml) were hydrogenated over pre-reduced 5% platinum oxide-on-carbon (0.3g) and 10%-palladium oxide-on-carbon (50% paste with H2O, 0.35g) until uptake of hydrogen ceased. The catalyst was removed by filtration (Hyflo) and the residue purified by [PCS] eluting with EA - methanol triethylamine (94:5:1*89:10:1) to give, after trituration with ER the title ccmpound as a cream solid (652mg) m.p. 60-62°.
Analysis Found: C,68.75;H,8.45;N,3.25.
C^Hj^FNO,, requires C,68.7;H,8.15;N,3.35%. 4 Example 60 4-Hydroxy-g1-f 116—[3-(4-methoxyphenyl)propoxy)-1methylhexyl]amino]methyl]-1,3-benzenedimethanol Λ solution of Intermediate 1 (1.45g) and Intermediate 65 (0.954g) in acetic acid (0.311g) and methanol (22ml) was treated with sodium cyanoborohydride (0.228g) at RT. The mixture was stirred for 16h, and poured into 8% aqueous NaHC03 (30ml) and extracted with EA (3x30ml).
The combined dried (Na2SO4) extracts were evaporated to give an oil (1.06g) which was purified by [FCS]II). The resulting oil was triturated with ER (25ml) and evaporated to give the title conpound as a white solid (0.713g) m.p. 75°-77°. T.l.c. [I] Rf 0.19.
Example 61 cJ-[ [ [1 ,l-Dimethyl-5-(3-phenylpropoxy)pentyl]amino]methyl]-4-hydroxy-r Ί,3-benzened imethanol A solution of Intermediate 67 (0.70q) in ethanol (35ml) was hydrogenated over 5% platinum on charcoal (0.2g) for 30min, filtered and evaporated. The residue was triturated with CX - ER 9:1 to give the title compound as a white solid (0.51g) m.p. 67-69°.
T.l.c. [M] Rf 0.3.
Example 62 σ1-ί[[1,l-Dimethyl-6-(2-phenylethoxy)hexyl)amino]methyl-4-hyaroxy-l,3benzened imethanol A solution of methyl 5-(brcmoacetyl)-2-hydroxybenzoate (2.2g) Intermediate 70 (2.0g) and N,N-diisopropyl ethylamine (1.16g) in EA (40ml) was refluxed for 3h, filtered and evaporated. The residue in ER (50ml) was filtered and the filtrate added dropwise to a suspension of LiAlH4 (1.6g) to ER (100ml) at 0°. The mixture was stirred at RT for 2h, treated cautiously with HjO (10ml), acidified to pHl with hydrochloric acid (2M), and basified to pH8 with solid K2CO3. The resulting slurry was extracted with CHC13 (4x200ml) and the dried extract was evaporated. The residue was purified on a column of silica (Merck 9385; 150mlj to give the title compound as a beige solid (0.325 m.p. 68-71°. T.l.c. [M] Rf 0.2.
Exanple 63 (R)-(-)-4-Hydroxy-o1-[[[6-(3-phenylpropoxy)hexyl]amino]methyl]-l,3- benzened imethanol 5 η Intermediate 77 (750mg) was hydrogenated in absolute ethanol (60ml) wer pre-reduced 10% palladium Oxide on carbon (50% paste, 150mg). After 2h, uptake of hydrogen (70ml) ceased. The catalyst was removed by filtration through Hyflo and the filtrate was concentrated in vacuo.. 10 The crude product was purified by [PCS] using EA-methanol-triethylamine 80:20:1 as eluant to give the title compound as a very viscous oil (270mg). Specific Rotation [alggg ~ -25.7° (c = 0.3 CHCl^) T.l.c. (EA-methancl-triethylamine 00:20:1) Rf = 0.22 Analysis Found: C,71.44;H,8.34;N,3.40. C2mH35NOi4reQuires C,71.79;H,8.79;N,3.49%. 15 Exanple 64 4-Hydroxy-a1-[ [ [6-phenylpropoxy)hexyl] aminolmethyl]-1,3- benzened imethanol 20 (a) 1- [4-Hydroxy-3- (hydroxymethyl) phenyl] -2- [ 6- (3-phenylpropoxy) hexyl] (phenylmethyl)amino]ethanone Ν,Ν-Diisopropylethylamine (2.77g) in CH2C12 (5ml) was added to a stirred suspension of 2-bromo-l-[4-hydroxy-3-(hydroxymethyl )phenyl]ethanone (2.5g) and Intermediate 22 (4.15g) in CH2C12 (30ml). The solution was kept at 23° for 24h, washed with H2O (5x17.5ml) and 25 evaporated in vacuo to give the crude product (a) as an oil. T.l.c. (isopropyl acetate : light petroleum, b.p. 60-80°, 1:1) Rf 0.4. .¾ (b) 4-Hvdroxy-a1-[[[6-(3-phenylprapoxy)hexyl]amino]methyl-l,3- benzened imethanol * 30 A solution of the crude product (a) in absolute ethanol (120ml) was hydrogenated at 40° and atmospheric presure over 10% palladium on carbon (O.lg) and 10% platinum on carbon (O.lg) catalysts. The mixture was filtered through Hyflo and evaporated to give an oil. lhe oil was I 35 dissolved in EA, the solution evaporated under reduced pressure and the residual oil was triturated with EA (5ml) to give the title compound as a white solid m.p. 81-82.5°. T.l.c. (EA:CH3OH:NH3 30:10:1) Rf 0.35.
The stimulant action at 32-adrenoreceptors of compounds of the invention was determined using the following: GUINEA-PIG TRAaiEAL STRIP PREPARATION 5 Tracheal rings were mounted in a superfusion apparatus, and continuously superfused with oxygenated physiological (Kreb’s) r solution containing indcmethacin (2.4xlO"6M) and atropine (4x10-7M) at 37° at a rate of 2ml/min. Changes in tension of the preparation were measured using an isometric strain gauge. 10. Preparations were contracted for the duration of the test by the inclusion of prostaglandin F2a (2.9xl0-6M)) in the superfusion fluid. Two bolus dose-effect curves to the standard, isoprenaline, (lxlO12-lxlO"9 moles) were obtained at the start of each test in a cumulative fashion, allowing the relaxation obtained with each 15 to reach its own maximum before the next increment was made. On completion of this dose-effect curve, sufficient time was allowed for the tissue to recover (15-3Qmin). After this time, sequential concentration-effect curves were constructed for first isoprenaline and then the test ccnpound. These were constructed as follows: a 20 lew concentration (isoprenaline 3x10 10M; test conpound 1x1010M) was infused until any response obtained had reached its maximum, then the infusion was stopped and the tissue allowed to recover for a maximum of 30min. After this period the procedure was repeated using progressively increasing concentrations of agonist, and in this way, whole concentration-effect curves obtained.
Potency was determined by comparison of the concentration-effect curve thus constructed with that previously obtained for (isoprenaline *. isoprenaline and expressed as equipotent concentration = « *·«· 5¾ iXrSST' «letted.
Eviration of action was also measured for each response, time taken from stepping the infusion to 50% recovery. and is the Graphs were drawn for duration times against response magnitude, and frcm these, duration times for 50% maximum responses were determined.
The ability of compounds of the invention to afford protection against histamine-induced bronchoconstriction was demonstrated using the following: CONSCIOUS GUINEA-PIG TEST The principle of the method is that bronchoconstriction leads to a decrease in tidal volume, and hence to an increase in respiratory rate.. Guinea-pigs were placed in a whole body plesythmograph i.e. a chamber separated, by means of a collar, into 2 parts - a head chamber and a body chamber. Pressure changes in the body chamber were monitored by means of a low pressure transducer, from which was derived a continuous, linear recording of respiratory rate by means of an instantaneous ratemeter connected to a chart recorder. The head chamber was connected to an expansion chamber into which a histamine aerosol was driven frcm a solution of set concentration (usually 5mg/ml) for a predetermined period (usually 10-15seconds). At the end of this period, the aerosol was switched off, but the guinea pig was left in contact with the aerosolized histamine still in the expansion chamber until his respiratory rate increased by 40%, or for a total of 4 min, whichever was the sooner. The degree of bronchoconstriction was expressed in terms of the area under the respiratory rate curve. Guinea-pigs were challenged at intervals until their rate responses were constant, then they were given a dose of the test compound by either aerosol or oral route, and the response to histamine reassessed first at 30 min post dose, and then at intervals thereafter for up to 24h post dose. By testing a range of doses of the test compound, a dose-relationship in the maximum protection was determined, and the time taken (up to 24h) for the response to histamine challenge to return to pre-test compound protection levels determined. Each dose of each test compound was tested in at least 4 animals.
The following are examples of suitable formulations of compounds of the invention. The term active ingredient is used herein to represent a compound of the invention and can be, for example, the compound of Example 2.
Tablets These may be prepared by the normal methods such as wet Γ granulation or direct compression. A. Direct Compression mg/tablet 10 Active ingredient 2.0 Microcrystalline Cellulose USP 196.5 Magnesium Stearate BP 1.5 Compression weight 200.0 The active ingredient is sieved through a suitable sieve, 15 blended with the excipients and compressed using 7mm diameter punches.
Tablets of other strengths may be prepared by altering the ratio of active ingredient to microcrystalline cellulose or the compression weight and using punches to suit.
B. Wet Granulation mg/tablet Active ingredient 2.0 Lactose BP 151.5 Starch BP 30.0 Pregelatinised Maize Starch BP 15.0 Magnesium Stearate BP 1.5 Compression weight 200.0 The active ingredient is sieved through a suitable sieve and blended with lactose, starch and pregelatinised maize starch. Suitable volumes of purified water are added and the powders are granulated. After drying, the granules are screened and blended with the magnesium stearate. The granules are then compressed into tablets using 7mm diameter punbhes.
Tablets of other strengths may be prepared by altering the ratio of active ingredient to lactose or the compression weight and using punches to suit.
C. For buccal administration mg/tablet Active ingredient 2.0 Lactose BP 94.8 Sucrose BP 86.7 Hydroxypropylmethylcellulose 15.0 Magnesium Stearate BP 1.5 Compression weight 200.0 The active ingredient is sieved through a suitable sieve and blended with the lactose, sucrose and hydroxypropylmethylcellulose. Suitable volumes of purified water are added and the powders are granulated. After drying, the granules are screened and blended with the magnesium stearate. The granules are then compressed into tablets using suitable punches.
The tablets may be film coated with suitable film forming materials, such as hydroxypropyl methylcellulose, using standard techniques. Alternatively the tablets may be sugar coated.
Capsules mg/capsules Active ingredient 2.0 * Starch 1500 97.0 Magnesium Stearate BP 1.0 Fill weight 100.Ό ♦ A form of directly compressible starch.
The active ingredient is sieved and blended with the excipients. The mix is filled into size No. 2 hard gelatin capsules using suitable machinery. Other doses may be prepared by altering the fill weight and if necessary changing the capsule size to suit.
Syrup This may be either a sucrose or sucrose free presentation.
A. Sucrose S^rup mg/5m1 dose Active ingredient 2.0 Sucrose BP 2750.0 Glycerine BP 500.0 in Buffer Flavour Colour Preservative ) ) ) ) as required Purified Water BP to 5.0ml The active ingredient, buffer, flavour, colour and preservative are dissolved in some of the water and the glycerine is added. The remainder of the water is heated to dissolve the sucrose and is then cooled. The two solutions are combined, adjusted to volume and mixed. The syrup produced is clarified by filtration.
Sucrose-Free mg/5ml dose Active ingredient 2 . Omg Hydroxypropyl methylcellulose USP (viscosity type 4000) 22.5mg Buffer ) Flavour ) Colour ) as required Preservative ) Sweetener ). Purified Water BP to 5.0ml 3C The hydroxypropyl methylcellulose is dispersed in hot water, cooled and then mixed with an aqueous solution containing the active ingredient and the other components of the formulation. The resultant solution is adjusted to volume and mixed. The syrup produced is clarified by filtration.
Metered Dose Pressurised Aerosol A. Suspension Aerosol mg/metered dose Per can Active ingredient micronised 0.100 26.4Omg 5 Oleic Acid BP 0.010 2.64mg Trichlorofluoromethane BP 23.64 5.67g Dichlorodifluoromethane BP 61.25 14.70g The active ingredient is micronised in a fluid energy mill to a fine particle size range. The Oleic Acid is mixed with the Trichlorofluoromethane at a temperature of -15°C and the micronised drug is mixed into the solution with a high shear mixer. The suspension is metered into aluminium aerosol cans and suitable metering valves, delivering 85mg of suspension are crimped onto the cans and the Dichlorodifluoromethane is pressure filled into the cans through the valves.
B. Solution Aerosol /metered dose Per can Active ingredient 0.100 24.Omg Ethanol BP 7.500 l.'80g Trichlorofluoromethane BP 18.875 4.53g Dichlorodifluoromethane BP 48.525 11.65g Oleic acid BP, or a suitable surfactant e.g. (sorbitan trioleate) may also be included. Span 85 The active ingredient is dissolved in the ethanol together with the oleic acid or surfactant if used. The ilcoholic solution is metered into suitable aerosol containers followed by the trichlorofluoromethane. Suitable metering valves are crimped onto the containers and dichlorodi30 fluoromethane is pressure filled into them through the valves.
Suppositories Active ingredient 2.0mg * Witepsol(Trade Mark) H15 to 1. Og * A. proprietary grade of Adeps Solidus Ph. Eur. r A suspension of the active ingredient in molten Witepsol is prepared and filled, using suitable machinery, into lg size suppositary moulds.
Injection for Intravenous Administration mg/ml Active ingredient 0.5mg Sodium Chloride BP as required Water for Injection BP to 1.0ml Sodium chloride may be added to adjust the tonicity of the solution and the pH may be adjusted, using acid or alkali, to that of optimum stability and/or facilitate solution of the active ingredient. Alternatively suitable buffer salts may be used.
The solution is prepared, clarified and filled into appropriate size ampoules sealed by fusion of the glass.
The injection is sterilised by heating in an autoclave using one of the acceptable cycles. Alternatively the .. solution may be sterilised by filtration and filled into sterile ampoules under aseptic conditions. The solution may be packed under an inert atmosphere of nitrogen or other suitable gas.
Inhalation Cartridges mg/cartridge Active ingredient micronised 0.200 Lactose BP . to 25.0 The active ingredient is micronised in a fluid energy mill to a fine particle size range prior to blending with normal tabletting grade lactose in a high energy mixer. The powder blend is filled into No. 3 hard gelatin capsules on a suitable encapsulating machine.
The contents of the cartridges are administered using a pcwder inhaler such as the Glaxo Botahaler (Registered Trade Mark).

Claims (20)

CLAIMS :
1. Compounds of the general formula (I) HOCH OH R' CHCH 2 NHC (CH 2 ) -0- (CII 2 ) n “Ar 2 1,, (I) wherein 5 m is an integer from 2 to 8 and n is an integer from 1 to 7 with the proviso that the sum total of m+n is 4 to 12; Ar represents a phenyl group which may be unsubstituted or substituted by one or two substituents 10 selected from halogen atoms, C^_ 3 alkyl and Cj_ 3 alkoxy groups, or by an alkylenedioxy group of formula -O(CH 2 )p0- where p is 1 or 2; and 1 2 R and R , which may be the same or different, each represents a hydrogen atom or a C^_ 3 alkyl 15 group with the proviso that the sum total of carbon 1 2 atoms xn R and R is not more than 4; and physiologically acceptable salts and solvates thereof
2. Compounds according to claim 1, wherein m is 3 and n is 6; or m is 4 and n is 3, 4 or 5; or m is 5 and 20 n is 2 , 3, 4 or 5; or m is 6 and n is 2 or 3.
3. Compounds according to claim 1, wherein the sum total of m+n is 7, 8, 9 or 10.
4. Compounds according to any of claims 1 to 3 , 1 2 wherein R and R , which may be the same or different, each represents a hydrogen atom or a methyl group.
5. Compounds according to any of claims 1 to 4, wherein Ar represents an unsubstituted phenyl group or a phenyl group substituted by one substituent selected from chlorine and fluorine atoms, methoxy and methyl groups. Compounds of the general formula (Ia) : HOCH 2 HQ CHCH,NHC(CH~) -0-(CH,) -Ar I & . i m ζ n ' * 2 OH R (la) wherein 1 2 R and R are as defined for general formula I in claim 1; m is an integer from 3 to
6. And n is an integer from 2 to 6 with the proviso that the sum total of m+n is 7 to 10 inclusive; and Ar is phenyl or phenyl substituted by a methyl or methoxy group or a fluorine or chlorine atom; and the physiologically acceptable salts and solvates thereof.
7. Compounds of the general formula (Ia) according to 1 2 claim 6, wherein R is a hydrogen atom and R is a hydrogen atom or a methyl group.
8. Compounds of the general formula Ia according to 1 2 claim 6, wherein R and R , which may be the same or different is each a hydrogen atom or a methyl group, m is 4 of 5, n is 2, 3 or 4 and Ar is phenyl or phenyl substituted by a chlorine or fluorine atom or a methoxy or methyl group.
9. 4-Hydroxy-a 1 [[[6-(4-phenylbutoxy)hexyl]aminolmethyl]1,3-benzenedimethanol and physiologically acceptable salts thereof.
10. 4-Hydroxy-<* 1 -[[[6(4-phenylbutoxy)hexyl]amino]methyl]-l,3-benzenedimethanol. l-hydroxy-2-naphthalenecarboxylate.
11. Compounds of the general formula I according to claim 1 selected frcm 4-hydroxy-oA[ [[6-(3-phenylpropoxy )hexyljaminojmethyl]-l,3-benzenedimethanol; 4-hydroxy-a 1 -[ [ [6-(2-phenylethoxy )hexyl ]aminolmethyl] -1,3-benzenedimethanol; 4-hydroxy-a 1 -( [ [ 5-(4 -phenyl butoxy Jpentyl]amino Jmethyl ] -1,3-benzenedimethanol 4-hydroxy-a 1 -[[[l-methyl-6-(2-phenylethoxy)hexyl]aminolmethyl]-l,3-benzenedimethanol; 4-hydroxy-a 1 -[[[1-methyl-5-(3-phenylpropoxy)pentyl]amino]methyl]-l,3-benzenedimethanol; 4-hydroxy-a 1 -[[[l-methyl-5-(4-phenylbutoxy)pentyl]amino]methyl]-l,3-benzenedimethanol; 4-hydroxy-a 1 -[[[l-ethyl-6-(2-phenylethoxy)hexyl]aminolmethylj -1,3-benzenedimethanol; [[1,l-dimethyl-6-(2-phenylethoxy)hexylJamino]methyl-4-hydroxy-l,3-benzenedimethanol; a^-f[[6-[2-(4-fluorophenyl)ethoxy]-l-methylhexyl)aminojmethyl]-4-hydroxy-l,3-benzenedimethanol; 4-hydroxy-a 1 -[[[6-[3-(4-methoxyphenyl) propoxy]-1methylhexyl]amino]methyl]-l,3-benzenedimethanol; 4-hydroxy-a 1 -[[[1-methy1-6-(4-phenylbutoxy)hexyl ,amino]methyl]-l,3-benzenedimethanol; 4-hydroxy-a -[[[6-[2-(4-methylphenyl)ethoxy,hexyl ,amino,methyl ,-1,3-benzenedimethanol; α 1_ [([6-[2-(3-chlorophenyl)ethoxy,hexyl,amino,methyl]4-hydroxy-l,3-benzenedimethanol; 4-hydroxy-a 1 [[[6-[2-(4-methoxyphenyl)ethoxy]hexyl]amino,-methyl,-1,3-benzenedimethanol; e^ - CC[6-[3-(4-fluoropheny1) propoxy]hexyl]amino]methyl]-4-hydroxy-l,3-benzenedimethanol; and the physiologically acceptable salts thereof.
12. A pharmaceutical composition comprising at least one compound of general formula (I) as defined in any of claims 1 to 11 or a physiologically acceptable salt or solvate thereof, together with a physiologically acceptable carrier or excipient.
13. A composition as claimed in claim 12 in a form suitable for administration by inhalation or insufflation.
14. A composition as claimed in claim 12 in a form suitable for oral, buccal, parental, topical or rectal administration.
15. A composition as claimed in claim 13, presented as a dry powder, an aerosol spray or in a form for delivery from a nebuliser.
16. A process for the preparation of a compound of general formula (I) as defined in claim 1 or a physiologically acceptable salt or solvate thereof, which process comprises: (1) in order to obtain a compound of general formula (I) in which R 1 is a hydrogen atom, alkylating an amine of general formula (II): If (II) T7 ο C ΖΓ (wherein R , R and R each represents a hydrogen 4 atom or a protecting group and R is a hydrogen atom) with an alkylating agent of general formula (III): LCH^CH^OfCH^Ar (HI) (wherein m, n, R and Ar are as defined in claim 1 and L is a leaving group) or with a compound of general formula (IV) : R 2 CO(CH 2 ) m -0-(CH 2 ) n Ar (IV) 10 (wherein R , m, n and Ar are as defined in claim 1) in the presence of a reducing agent, followed by removal of any protecting groups where present; or (2) reducing an intermediate of general formula (VI) : (VI) (wherein n and Ar are as defined in claim 1, r5 is a hydrogen atom or a protecting group, and at least one of X, X 1 , X 2 X 3 and X 4 represents a reducible group and the other group or groups have the meanings: X is -CH 2 0r6, is -CH(OH)X 2 is -CH2NR 3 , and X 3 is -CR 3 * 2 (CH^^and X 4 is -(CH2)~ n- ^ where R& , R 3 , R 2 , R 3- and m are as ί 5 defined in claim 1) « or a protected derivative thereof followed by lemoval of any protecting groups where present; or (3, reacting a compound of general formula (VII) : (VII) (wherein Z represents a group -CH - CH 9 or 0 5 6 -CHCH~L where R and R , which may be the same or I 2 OH different, each represents a hydrogen atom or a protecting group and L is a leaving group) with an amine of general formula (VIII): 7 R 1 1 I Y i NHC(CH 2 ) m -0-(CH 2 ) n -Ar (VIII) I 2 R* (wherein Y 3, is a hydrogen atom or a group convertible 1 2 thereto by catalytic hydrogenation and R , R , m, n and Ar are as defined in claim 1) followed by removal of any protecting groups where present; or 7 9 a protected derivative of general (4) deprotecting CHCH o NR 3 C(CH o ) -0-(CH-)“Ar I i ι z m z n · 2 OH R (IX) 1 2 (wherein R , R , m, n and Ar are as defined in 3 5 6 claim 1 and R , R and R are each a protecting group or a hydrogen atom provided that at least one is a protecting group; and, if desired, converting the resulting compound of general formula (I) or a salt thereof into a physiologically acceptable salt or solvate thereof.
17. Conpounds of general formula (I) as defined in claim 1, substantially as herein described with particular reference to the examples
18. A pharmaceutical composition according to claim 12, substantially as hereinbefore described and exemplified.
19. A process for the preparation of a compound of general formula (I) given and defined in claim 1 or a physiologically acceptable salt or solvate thereof, substantially as hereinbefore described and exemplified.
20. A compound of general formula (I) given and defined in claim 1 or a physiologically acceptable salt or solvate thereof, whenever prepared by a process claimed in a preceding claim.
IE965/84A 1983-04-18 1984-04-18 Phenethanolamine derivatives IE57237B1 (en)

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Families Citing this family (180)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ZW6584A1 (en) * 1983-04-18 1985-04-17 Glaxo Group Ltd Phenethanolamine derivatives
PT80304B (en) 1984-04-17 1987-03-16 Glaxo Group Ltd Process for preparing phenethanolamine compounds
US4943591A (en) * 1984-10-17 1990-07-24 Glaxo Group Limited Dichloroaniline derivatives
GB8525321D0 (en) * 1985-10-15 1985-11-20 Glaxo Group Ltd Chemical compounds
GB8525484D0 (en) * 1985-10-16 1985-11-20 Glaxo Group Ltd Chemical compounds
EP0223410A3 (en) * 1985-10-16 1987-11-19 Glaxo Group Limited Ethanolamine derivatives
GB8525483D0 (en) * 1985-10-16 1985-11-20 Glaxo Group Ltd Chemical compounds
EP0220054A3 (en) * 1985-10-16 1987-12-02 Glaxo Group Limited Ethanolamine derivatives
EP0278727A3 (en) * 1987-02-10 1990-03-14 Glaxo Group Limited 1-(4-amino-3-chloro-5-trifluoromethylphenyl)-2-(substituted amino)ethanol derivatives and their use in the treatment of respiratory disease
EP0286242A3 (en) * 1987-03-12 1989-08-09 Glaxo Group Limited Ethanolamine derivates, processes for their preparation and pharmaceutical compositions containing them
GB8718938D0 (en) * 1987-08-11 1987-09-16 Glaxo Group Ltd Chemical compounds
GB8718940D0 (en) * 1987-08-11 1987-09-16 Glaxo Group Ltd Chemical compounds
ES2039646T3 (en) * 1987-11-13 1993-10-01 Glaxo Group Limited PHENETHANOLAMINE DERIVATIVES.
NZ227365A (en) * 1987-12-18 1990-10-26 Glaxo Group Ltd Aromatic amino ethers and pharmaceutical compositions
ZA889405B (en) * 1987-12-18 1989-12-27 Glaxo Group Ltd Ethanolamine derivatives
GB8909273D0 (en) * 1989-04-24 1989-06-07 Glaxo Group Ltd Chemical compounds
GB2230775A (en) * 1989-04-24 1990-10-31 Glaxo Group Ltd Phenethanolamine compounds
US5290815A (en) * 1989-09-07 1994-03-01 Glaxo Group Limited Treatment of inflammation and allergy
EP0416925A3 (en) * 1989-09-07 1991-09-25 Glaxo Group Limited Use of 4-hydroxy-alpha 1-(((6-(4-phenylbutoxy)hexyl)amino)methyl)-1,3-benzenedimethanol or its salts in the treatment of allergy and inflammation
JP3042866B2 (en) * 1989-09-08 2000-05-22 グラクソ・グループ・リミテッド Respiratory disease drug
US5208226A (en) * 1989-09-08 1993-05-04 Glaxo Group Limited Medicaments
IL95590A (en) * 1989-09-08 1996-06-18 Glaxo Group Ltd Pharmaceutical compositions comprising salmeterol and fluticasone propionate
US5270305A (en) * 1989-09-08 1993-12-14 Glaxo Group Limited Medicaments
IE903614A1 (en) * 1989-10-10 1991-04-24 Glaxo Group Ltd Phenethanolamine Compound
SK280967B6 (en) 1990-03-02 2000-10-09 Glaxo Group Limited Inhalation device
TW197380B (en) 1990-03-02 1993-01-01 Glaxo Group Ltd
US6536427B2 (en) 1990-03-02 2003-03-25 Glaxo Group Limited Inhalation device
US5919827A (en) * 1990-07-11 1999-07-06 Sepracor Inc. Method for treating asthma using optically pure R(-) salmeterol
GB9026005D0 (en) * 1990-11-29 1991-01-16 Glaxo Group Ltd Drug material suitable for micronisation
CN1056974C (en) * 1992-02-11 2000-10-04 格拉克索公司 Drug material suitable for micronisation
AU1229892A (en) * 1992-02-11 1993-09-03 Glaxo Group Limited Benzenedimethanol derivative suitable for micronisation
AP323A (en) * 1992-05-08 1994-03-07 Glaxo Group Ltd Drug material suitable for micronisation.
GB9215274D0 (en) * 1992-07-17 1992-09-02 Scras Derivatives of(phenylethyl-beta-ol)amine
ES2065269B1 (en) * 1993-05-11 1995-10-01 S A L V A T Lab Sa 6- (4- (FENILBUTOXI) HEXILAMINOMETIL-4-HIDROXI-A1, A3-BENCENODIMETANOL. PROCEDURE FOR THE OBTAINING OF THE SAME AND NEW INTERMEDIATES USED IN ITS PREPARATION.
JP3792713B2 (en) * 1993-12-10 2006-07-05 ノバルティス アクチェンゲゼルシャフト New substituted oxazolidine
GB9507768D0 (en) 1995-04-13 1995-05-31 Glaxo Group Ltd Method of apparatus
HUP9800641A3 (en) 1995-04-14 2001-04-28 Glaxo Wellcome Inc Res Triangl Metered dose inhaler for beclomethasone dipropionate
NZ306280A (en) 1995-04-14 1999-07-29 Glaxo Wellcome Inc Metered dose inhaler for salmeterol
PL180895B1 (en) 1995-04-14 2001-04-30 Glaxo Wellcome Inc Fluticazone propionate inhaler with dosis metering feature
DE69622166T2 (en) * 1995-04-14 2003-04-03 Smithkline Beecham Corp DOSING INHALATOR FOR ALBUTEROL
AU4967997A (en) 1996-12-02 1998-06-29 Chisso Corporation Optically active nitro alcohol derivatives, optically active amino alcohol derivates, and process for preparing the same
US6254882B1 (en) 1997-09-16 2001-07-03 Sepracor Inc. Methods and compositions for treating pulmonary disorders using optically pure (S)—salmeterol
IL139907A0 (en) * 1998-06-01 2002-02-10 Verbiscar Anthony J Topical transdermal treatments
ES2142771B1 (en) * 1998-09-28 2001-01-01 Vita Invest Sa NEW DERIVATIVES OF 6- (4-PHENYL-BUTOXI) HEXYLAMINE AND PROCEDURE FOR OBTAINING SALMETEROL.
JP2002541183A (en) 1999-04-14 2002-12-03 グラクソ グループ リミテッド Pharmaceutical aerosol formulation
EP2193808A1 (en) * 1999-08-21 2010-06-09 Nycomed GmbH Synergistic combination
GB0009609D0 (en) * 2000-04-18 2000-06-07 Glaxo Group Ltd Therapeutic compositions
GB0009613D0 (en) * 2000-04-18 2000-06-07 Glaxo Group Ltd Pharmaceutical compositions
GB0014546D0 (en) 2000-06-14 2000-08-09 Glaxo Group Ltd A novel process
GB0015043D0 (en) 2000-06-21 2000-08-09 Glaxo Group Ltd Medicament dispenser
US6759398B2 (en) * 2000-08-05 2004-07-06 Smithkline Beecham Corporation Anti-inflammatory androstane derivative
GB0019172D0 (en) 2000-08-05 2000-09-27 Glaxo Group Ltd Novel compounds
US6858593B2 (en) 2000-08-05 2005-02-22 Smithkline Beecham Corporation Anti-inflammatory androstane derivative compositions
US6777400B2 (en) 2000-08-05 2004-08-17 Smithkline Beecham Corporation Anti-inflammatory androstane derivative compositions
US6787532B2 (en) 2000-08-05 2004-09-07 Smithkline Beecham Corporation Formulation containing anti-inflammatory androstane derivatives
SK287576B6 (en) * 2000-08-05 2011-03-04 Glaxo Group Limited 6Alpha,9alpha-difluoro-17alpha-[(2-furanylcarboxyl)oxy]-11beta- hydroxy-16alpha-methyl-3-oxo-androst-1,4-diene-17beta-carbothioic acid S-fluoromethyl ester as an anti-inflammatory agent, method for the production, farmaceutical composition containing thereof, the use thereof and intermediates
US6750210B2 (en) 2000-08-05 2004-06-15 Smithkline Beecham Corporation Formulation containing novel anti-inflammatory androstane derivative
US6858596B2 (en) 2000-08-05 2005-02-22 Smithkline Beecham Corporation Formulation containing anti-inflammatory androstane derivative
US6777399B2 (en) 2000-08-05 2004-08-17 Smithkline Beecham Corporation Anti-inflammatory androstane derivative compositions
AU2001289126A1 (en) 2000-09-18 2002-04-02 Glaxo Group Limited Metered dose inhaler can coated two or more times with fluorocarbon polymers
GB0103630D0 (en) 2001-02-14 2001-03-28 Glaxo Group Ltd Chemical compounds
WO2002070490A1 (en) * 2001-03-08 2002-09-12 Glaxo Group Limited Agonists of beta-adrenoceptors
IL157580A0 (en) * 2001-03-20 2004-03-28 Glaxo Group Ltd Inhalation drug combination
WO2002076933A1 (en) * 2001-03-22 2002-10-03 Glaxo Group Limited Formailide derivatives as beta2-adrenoreceptor agonists
UA77656C2 (en) 2001-04-07 2007-01-15 Glaxo Group Ltd S-fluoromethyl ester of 6-alpha, 9-alpha-difluoro-17-alpha-[(2-furanylcarbonyl)oxy]-11-beta-hydroxy-16- alpha-methyl-3-oxoandrosta-1,4-dien-17-beta-carbothioacid as anti-inflammatory agent
US20030055026A1 (en) 2001-04-17 2003-03-20 Dey L.P. Formoterol/steroid bronchodilating compositions and methods of use thereof
US6667344B2 (en) 2001-04-17 2003-12-23 Dey, L.P. Bronchodilating compositions and methods
AR033290A1 (en) * 2001-04-30 2003-12-10 Glaxo Group Ltd ANDROSTANO ANTIINFLAMATORY DERIVATIVES
CA2449103A1 (en) * 2001-06-01 2002-12-12 Tendskin Company Topical compositions for veterinary uses
US6680345B2 (en) 2001-09-14 2004-01-20 Boehringer Ingelheim Pharma Kg Salicylic acid salts of salmeterol
ES2438985T3 (en) * 2001-09-14 2014-01-21 Glaxo Group Limited Inhalation formulation comprising phenetanolamine derivatives for the treatment of respiratory diseases
WO2003024440A1 (en) * 2001-09-14 2003-03-27 Boehringer Ingelheim Pharma Gmbh & Co. Kg Salicylic acid salts, methods for the production and use thereof as medicaments
US20030229058A1 (en) * 2001-11-13 2003-12-11 Moran Edmund J. Aryl aniline beta2 adrenergic receptor agonists
US6653323B2 (en) 2001-11-13 2003-11-25 Theravance, Inc. Aryl aniline β2 adrenergic receptor agonists
TWI249515B (en) 2001-11-13 2006-02-21 Theravance Inc Aryl aniline beta2 adrenergic receptor agonists
US20050175545A1 (en) * 2002-02-04 2005-08-11 Keith Biggadike Formulation for inhalation comprising a glucocorticoid and a beta 2-adrenoreceptor agonist
GB0202635D0 (en) * 2002-02-05 2002-03-20 Glaxo Wellcome Mfg Pte Ltd Formulation containing novel anti-inflammatory androstane derivative
US6756508B2 (en) 2002-03-04 2004-06-29 Boehringer Ingelheim Pharma Gmbh & Co. Kg Cinnamic acid salts, processes for their preparation, and their use as medicaments
WO2003074469A1 (en) * 2002-03-04 2003-09-12 Boehringer Ingelheim Pharma Gmbh & Co. Kg Novel cinnamate salts, method for production and use thereof as medicaments
US6835857B2 (en) 2002-03-05 2004-12-28 Boehringer Ingelheim Pharma Gmbh & Co. Kg Process for the manufacture of 4-(6-bromohexyloxy)-butylbenzene
DE10209583B4 (en) * 2002-03-05 2006-01-19 Boehringer Ingelheim Pharma Gmbh & Co. Kg Process for the preparation of 4- (6-bromohexyloxy) -butylbenzene
WO2003088961A1 (en) * 2002-04-19 2003-10-30 Yissum Research Development Company Of The Hebrew University Of Jerusalem Beta-agonist compounds comprising nitric oxide donor groups and reactive oxygen species scavenger groups and their use in the treatment of respiratory disorders
AU2003222841A1 (en) 2002-04-25 2003-11-10 Glaxo Group Limited Phenethanolamine derivatives
JP2005527618A (en) 2002-05-28 2005-09-15 セラヴァンス インコーポレーテッド Alkoxyaryl β2 adrenergic receptor agonist
GB2389530B (en) 2002-06-14 2007-01-10 Cipla Ltd Pharmaceutical compositions
GB0217225D0 (en) * 2002-07-25 2002-09-04 Glaxo Group Ltd Medicinal compounds
US20040023935A1 (en) * 2002-08-02 2004-02-05 Dey, L.P. Inhalation compositions, methods of use thereof, and process for preparation of same
DE10249576B3 (en) * 2002-10-24 2004-04-08 Boehringer Ingelheim Pharma Gmbh & Co. Kg Preparation of levo-salbutamol, useful as bronchodilator, by asymmetrical catalytic hydrogenation of its ketone precursor in presence of rhodium and chiral phosphine
GB0225030D0 (en) * 2002-10-28 2002-12-04 Glaxo Group Ltd Medicinal compounds
JP2006503888A (en) * 2002-10-28 2006-02-02 グラクソ　グループ　リミテッド Phenetanolamine derivatives for the treatment of respiratory diseases
GB0225535D0 (en) * 2002-11-01 2002-12-11 Glaxo Group Ltd Medicinal compounds
US20040109826A1 (en) * 2002-12-06 2004-06-10 Dey, L.P. Stabilized albuterol compositions and method of preparation thereof
EP1575648A4 (en) * 2002-12-18 2007-07-04 Glaxo Group Ltd Drug delivery system with vented mouthpiece
GB0303396D0 (en) 2003-02-14 2003-03-19 Glaxo Group Ltd Medicinal compounds
PE20040950A1 (en) * 2003-02-14 2005-01-01 Theravance Inc BIPHENYL DERIVATIVES AS AGONISTS OF ß2-ADRENERGIC RECEPTORS AND AS ANTAGONISTS OF MUSCARINAL RECEPTORS
WO2004089892A2 (en) * 2003-04-01 2004-10-21 Theravance, Inc. Diarylmethyl and related compounds having beta2 andrenergic receptor agonist and muscarinic receptor antagonist activity
US20040226556A1 (en) 2003-05-13 2004-11-18 Deem Mark E. Apparatus for treating asthma using neurotoxin
ATE435862T1 (en) * 2003-05-28 2009-07-15 Theravance Inc AZABICYCLOALKAN COMPOUNDS AS MUSCARINE RECEPTOR ANTAGONISTS
TWI359675B (en) * 2003-07-10 2012-03-11 Dey L P Bronchodilating β-agonist compositions
US20050026884A1 (en) * 2003-07-31 2005-02-03 Robinson Cynthia B. Combination of dehydroepiandrosterone or dehydroepiandrosterone-sulfate with a beta-agonist bronchodilator for treatment of asthma or chronic obstructive pulmonary disease
US20050113318A1 (en) * 2003-07-31 2005-05-26 Robinson Cynthia B. Combination of dehydroepiandrosterone or dehydroepiandrosterone-sulfate with a beta-agonist bronchodilator for treatment of asthma or chronic obstructive pulmonary disease
US20090285900A1 (en) * 2003-07-31 2009-11-19 Robinson Cynthia B Combination of dehydroepiandrosterone or dehydroepiandrosterone-sulfate with a beta-agonist bronchodilator for treatment of asthma or chronic obstructive pulmonary disease
EP1654312B1 (en) 2003-08-11 2014-01-15 Glaxo Group Limited Pharmaceutical metered dose inhaler and methods relating thereto
GB0319826D0 (en) * 2003-08-22 2003-09-24 Glaxo Group Ltd Process
AR045536A1 (en) * 2003-08-29 2005-11-02 Ranbaxy Lab Ltd INHIBITORS OF PHOSPHODIESTERASE TYPE -IV
TW200526547A (en) * 2003-09-22 2005-08-16 Theravance Inc Amino-substituted ethylamino β2 adrenergic receptor agonists
GB0324654D0 (en) * 2003-10-22 2003-11-26 Glaxo Group Ltd Medicinal compounds
GB0324886D0 (en) * 2003-10-24 2003-11-26 Glaxo Group Ltd Medicinal compounds
WO2005051931A2 (en) * 2003-11-26 2005-06-09 Ranbaxy Laboratories Limited Phosphodiesterase inhibitors
SE0303570L (en) * 2003-12-03 2005-06-04 Microdrug Ag Moisture-sensitive medical product
WO2005053647A1 (en) * 2003-12-03 2005-06-16 Microdrug Ag Medical product containing tiotropium
SE0303270L (en) * 2003-12-03 2005-06-04 Microdrug Ag Method of administration of tiotropium
GB0329182D0 (en) * 2003-12-17 2004-01-21 Glaxo Group Ltd Chemical compounds
TW200531692A (en) * 2004-01-12 2005-10-01 Theravance Inc Aryl aniline derivatives as β2 adrenergic receptor agonists
WO2005087192A2 (en) * 2004-03-12 2005-09-22 Cipla Limited Salmeterol inhalation formulations
CA2569395A1 (en) * 2004-06-03 2005-12-22 Theravance, Inc. Diamine .beta.2 adrenergic receptor agonists
WO2006014704A1 (en) * 2004-07-21 2006-02-09 Theravance, Inc. DIARYL ETHER β2 ADRENERGIC RECEPTOR AGONISTS
WO2006031556A2 (en) * 2004-09-10 2006-03-23 Theravance. Inc. Amidine substituted aryl aniline compounds
EP1949891A1 (en) 2004-10-12 2008-07-30 Generics (UK) Limited Process for the preparation of suspension aerosol formulations, wherein the particles are formed by precipitation inside an aerosol canister
EP1811981B1 (en) 2004-10-12 2008-08-13 Merck Generics (UK) Limited Process for the preparation of suspension aerosol formulations, wherein the particles are formed by precipitation inside an aerosol canister
GB0507165D0 (en) * 2005-04-08 2005-05-18 Glaxo Group Ltd Novel crystalline pharmaceutical product
ES2265276B1 (en) * 2005-05-20 2008-02-01 Laboratorios Almirall S.A. DERIVATIVES OF 4- (2-AMINO-1-HYDROXYETHYL) Phenol as agonists of the BETA2 ADRENERGIC RECEIVER.
DE102005033732B4 (en) * 2005-05-27 2014-02-13 Grünenthal GmbH Separation of stereoisomeric N, N-dialkylamino-2-alkyl-3-hydroxy-3-phenyl-alkanes
WO2007008427A2 (en) * 2005-07-08 2007-01-18 Xemplar Pharmaceuticals, Llc Aerosol compositions and methods
US8429052B2 (en) * 2005-07-19 2013-04-23 Lincoln National Life Insurance Company Method and system for providing employer-sponsored retirement plan
TWI274641B (en) * 2005-08-30 2007-03-01 Rexon Ind Corp Ltd Cutting machine
WO2007031838A1 (en) 2005-09-16 2007-03-22 Ranbaxy Laboratories Limited Substituted pyrazolo [3,4-b] pyridines as phosphodiesterase inhibitors
AU2006303124B2 (en) 2005-10-17 2013-03-28 Generics [Uk] Limited Novel process
CA2626612A1 (en) 2005-10-19 2007-04-26 Ranbaxy Laboratories Limited Pharmaceutical compositions of muscarinic receptor antagonists
WO2007045980A1 (en) * 2005-10-19 2007-04-26 Ranbaxy Laboratories Limited Compositions of phosphodiesterase type iv inhibitors
US7731106B2 (en) * 2006-01-04 2010-06-08 Nano Mist International, Llc Air driven delivery system for sprayable media
GB0602778D0 (en) * 2006-02-10 2006-03-22 Glaxo Group Ltd Novel compound
WO2007103970A2 (en) * 2006-03-07 2007-09-13 Endacea, Inc. Compositions and methods for treating respiratory disorders
ES2296516B1 (en) * 2006-04-27 2009-04-01 Laboratorios Almirall S.A. DERIVATIVES OF 4- (2-AMINO-1-HYDROXYETHYL) Phenol as agonists of the BETA2 ADRENERGIC RECEIVER.
US20070286814A1 (en) * 2006-06-12 2007-12-13 Medispray Laboratories Pvt. Ltd. Stable aerosol pharmaceutical formulations
GB0615108D0 (en) * 2006-07-28 2006-09-06 Glaxo Group Ltd Novel formulations
EA016567B1 (en) 2006-08-22 2012-05-30 Ранбакси Лабораториз Лимитед Matrix metalloproteinase inhibitors
WO2008035315A2 (en) * 2006-09-22 2008-03-27 Ranbaxy Laboratories Limited Inhibitors of phosphodiesterase type-iv
WO2008035316A2 (en) * 2006-09-22 2008-03-27 Ranbaxy Laboratories Limited Phosphodiesterase inhibitors
ES2302447B1 (en) * 2006-10-20 2009-06-12 Laboratorios Almirall S.A. DERIVATIVES OF 4- (2-AMINO-1-HYDROXYETHYL) Phenol as agonists of the BETA2 ADRENERGIC RECEIVER.
ES2306595B1 (en) 2007-02-09 2009-09-11 Laboratorios Almirall S.A. NAPADISYLATE SALT OF 5- (2 - ((6- (2,2-DIFLUORO-2-PHENYLETOXI) HEXIL) AMINO) -1-HYDROXYETHYL) -8-HYDROXYCHINOLIN-2 (1H) -ONE AS ADRENERGIC RECEIVER AGONIST BETA2 .
EP1958947A1 (en) 2007-02-15 2008-08-20 Ranbaxy Laboratories Limited Inhibitors of phosphodiesterase type 4
CN103497185A (en) 2007-03-14 2014-01-08 兰贝克赛实验室有限公司 Pyrazolo(3, 4-B)pyridine derivatives as phosphodiesterase inhibitors
EP2124943A1 (en) * 2007-03-14 2009-12-02 Ranbaxy Laboratories Limited Pyrazolo [3, 4-b]pyridine derivatives as phosphodiesterase inhibitors
US20080319086A1 (en) * 2007-06-20 2008-12-25 Protia, Llc Deuterium-enriched salmeterol
US20090048155A1 (en) 2007-08-15 2009-02-19 Endacea, Inc. Methods for preventing and treating tissue injury and sepsis associated with Yersinia pestis infection
ES2320961B1 (en) 2007-11-28 2010-03-17 Laboratorios Almirall, S.A. DERIVATIVES OF 4- (2-AMINO-1-HYDROXYETHYL) PHENOL AS BETA2 ADRENERGIC RECEIVER AGONISTS.
US9522916B2 (en) 2007-12-21 2016-12-20 Constance Neely Wilson A1 adenosine receptor antagonists
US8483831B1 (en) 2008-02-15 2013-07-09 Holaira, Inc. System and method for bronchial dilation
EP3311820A1 (en) 2008-02-26 2018-04-25 Sunovion Respiratory Development Inc. Method and system for the treatment of chronic obstructive pulmonary disease with nebulized anticholinergic administrations
US20100055045A1 (en) 2008-02-26 2010-03-04 William Gerhart Method and system for the treatment of chronic obstructive pulmonary disease with nebulized anticholinergic administrations
EP2111861A1 (en) 2008-04-21 2009-10-28 Ranbaxy Laboratories Limited Compositions of phosphodiesterase type IV inhibitors
AU2009244058B2 (en) * 2008-05-09 2015-07-02 Nuvaira, Inc Systems, assemblies, and methods for treating a bronchial tree
EP2127641A1 (en) 2008-05-26 2009-12-02 Inke, S.A. Micronisable form of salmeterol xinafoate
UY32297A (en) 2008-12-22 2010-05-31 Almirall Sa MESILATE SALT OF 5- (2 - {[6- (2,2-DIFLUORO-2-PHENYLITOXI) HEXIL] AMINO} -1-HYDROXYETHYL) -8-HYDROXYCHINOLIN-2 (1H) -ONA AS A RECEIVER AGONIST B (BETA ) 2 ACRENERGIC
EP2221055A1 (en) * 2009-02-18 2010-08-25 Almirall, S.A. 5-(2-{[6-(2,2-difluoro-2-phenylethoxy)hexyl]amino}-1-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one for the treatment of lung function
EP2228368A1 (en) 2009-03-12 2010-09-15 Almirall, S.A. Process for manufacturing 5-(2-{[6-(2,2-difluoro-2-phenylethoxy) hexyl]amino}-1-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one
US8815258B2 (en) 2009-05-29 2014-08-26 Pearl Therapeutics, Inc. Compositions, methods and systems for respiratory delivery of two or more active agents
CA2763939A1 (en) * 2009-05-29 2010-12-02 Pearl Therapeutics, Inc. Compositions for pulmonary delivery of long-acting muscarinic antagonists and long-acting b2 adrenergic receptor agonists and associated methods and systems
EP2493408B1 (en) 2009-10-27 2015-06-24 Holaira, Inc. Delivery devices with coolable energy emitting assemblies
US8911439B2 (en) 2009-11-11 2014-12-16 Holaira, Inc. Non-invasive and minimally invasive denervation methods and systems for performing the same
AU2010319477A1 (en) 2009-11-11 2012-05-24 Holaira, Inc. Systems, apparatuses, and methods for treating tissue and controlling stenosis
TR201000685A2 (en) 2010-01-29 2011-08-22 Bi̇lgi̇ç Mahmut Pharmaceutical preparations containing salmeterol and fluticasone.
US8367829B2 (en) 2010-05-10 2013-02-05 Gilead Sciences, Inc. Bi-functional pyrazolopyridine compounds
WO2011143105A1 (en) 2010-05-10 2011-11-17 Gilead Sciences, Inc. Bifunctional quinoline derivatives
BR112013002370A2 (en) 2010-07-30 2017-06-20 Ranbaxy Laboratories Ltd compound, pharmaceutical composition and process for preparing a compound
WO2012032546A2 (en) 2010-09-08 2012-03-15 Cadila Healthcare Limited Process for the preparation of salmeterol and its intermediates
JP2013540754A (en) 2010-09-24 2013-11-07 ランバクシー ラボラトリーズ リミテッド Matrix metalloproteinase inhibitor
EP2578570A1 (en) 2011-10-07 2013-04-10 Almirall, S.A. Novel process for preparing 5-(2-{[6-(2,2-difluoro-2-phenylethoxy)hexyl]amino}-1(r)-hydroxyethyl)-8-hydroxyquinolin-2(1h)-one via novel intermediates of synthesis.
EP2641900A1 (en) 2012-03-20 2013-09-25 Almirall, S.A. Novel polymorphic Crystal forms of 5-(2-{[6-(2,2-difluoro-2-phenylethoxy) hexyl]amino}-1-(R)-hydroxyethyl)-8-hydroxyquinolin-2(1h)-one, heminapadisylate as agonist of the ß2 adrenergic receptor.
CN103864629A (en) * 2012-12-13 2014-06-18 天津金耀集团有限公司 Refining method of Salmeterol xinafoate
US9398933B2 (en) 2012-12-27 2016-07-26 Holaira, Inc. Methods for improving drug efficacy including a combination of drug administration and nerve modulation
KR102391332B1 (en) 2013-03-15 2022-04-26 펄 테라퓨틱스 인코포레이티드 Methods and systems for conditioning of particulate crystalline materials
EP2815739B1 (en) 2013-06-17 2019-08-28 Arven Ilac Sanayi Ve Ticaret A.S. Inhalation composition filling method
CN104744271B (en) * 2013-12-26 2016-08-31 成都伊诺达博医药科技有限公司 A kind of new technology synthesizing Wei Lanteluo
US9447067B2 (en) 2014-10-03 2016-09-20 Amphastar Pahmaceuticals, Inc. Method of preparing intermediate of salmeterol
WO2016142582A1 (en) 2015-03-11 2016-09-15 Fermion Oy Process for the preparation of crystalline salmeterol and its xinafoate salt
IL309888A (en) 2021-07-09 2024-03-01 Astrazeneca Pharmaceuticals Lp Compositions, methods and systems for aerosol drug delivery
WO2023119093A1 (en) 2021-12-20 2023-06-29 Astrazeneca Ab Compositions, methods and systems for aerosol drug delivery
WO2024006226A1 (en) * 2022-06-26 2024-01-04 Alexander Shulgin Research Institute, Inc. N-substituted phenylalkylamines and their use as therapeutic agents

Family Cites Families (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR1451357A (en) * 1965-07-01 1966-01-07 Soc Ind Fab Antibiotiques Sifa New alcohols derived from ethano-9, 10 dihydro-9, 10 anthracene and method of preparation
GB1200886A (en) * 1966-09-23 1970-08-05 Allen & Hanburys Ltd Phenylaminoethanol derivatives
GB1321701A (en) * 1969-10-01 1973-06-27 Continental Pharma Amino-alcohols their salts and process for prepairing the same
US4137328A (en) * 1970-07-18 1979-01-30 Pfizer Inc. Phenyl-alkanolamine, alkylamine and α-aminoalkyl ketone derivatives as heart stimulants
AT310146B (en) * 1971-04-26 1973-09-25 Boehringer Sohn Ingelheim Process for the production of new N, N'-bis- (β-hydroxyarylethyl) -diaminoalkanes and their acid addition salts
US3879442A (en) * 1972-07-27 1975-04-22 Warner Lambert Co 5-hydroxy-{60 (substituted aminomethyl)-mu-xylene-{60 ,{60 -diols
GB1511159A (en) * 1975-07-10 1978-05-17 Leo A Amines preparation
GB1529972A (en) * 1975-07-29 1978-10-25 Allen & Hanburys Ltd Basic alcohols
US4160036A (en) * 1975-07-29 1979-07-03 Allen & Hanburys Limited 4-Hydroxy-1,3-benzenedimethanol derivatives
US4154761A (en) * 1976-02-09 1979-05-15 Allen & Hanburys Limited Pharmacologically active compounds
JPS52113934A (en) * 1976-03-19 1977-09-24 Eisai Co Ltd Phenethylamine derivatives and bronchodilator containing the same
US4233302A (en) * 1977-12-23 1980-11-11 Glaxo Group Limited Amine derivatives and pharmaceutical compositions containing them
DE2833140A1 (en) * 1978-07-28 1980-02-07 Boehringer Sohn Ingelheim NEW N-SUBSTITUTED HETEROCYCLES
US4160367A (en) * 1978-09-11 1979-07-10 General Motors Corporation Dual container additive dispenser for appliance
DE3061205D1 (en) * 1979-06-16 1983-01-05 Beecham Group Plc Secondary amines, their preparation and use in pharmaceutical compositions
FR2460919A1 (en) * 1979-07-11 1981-01-30 Prod Synthese Ste Indle AMINO-ETHERS OXIDES, PROCESS FOR PREPARING THEM AND THEIR THERAPEUTIC APPLICATION
US4288456A (en) * 1980-09-19 1981-09-08 E. R. Squibb & Sons, Inc. Compositions containing 1-aryl-5-(2-propenylamino)-1-penten-3-ones and method for treating inflammatory conditions
US4379166A (en) * 1981-08-03 1983-04-05 Schering Corporation Arylmethoxy-, arylmethylthio-, heteroarylmethoxy-, and heteroarylmethylthio-alkylaminoalcohols
EP0103830A3 (en) * 1982-09-22 1985-07-31 Bayer Ag Phenylethylemine derivatires as growth stimulators
ZW6584A1 (en) * 1983-04-18 1985-04-17 Glaxo Group Ltd Phenethanolamine derivatives
US4985459A (en) * 1984-02-08 1991-01-15 Richardson-Vicks, Inc. Analgesic and anti-inflammatory compositions comprising diphenhydramine and methods of using same
PT80304B (en) * 1984-04-17 1987-03-16 Glaxo Group Ltd Process for preparing phenethanolamine compounds

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